BioPAX pathway converted from "Signaling by NTRKs" in the Reactome database. Signaling by NTRKs Signaling by Neurotrophin Receptors This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Expression and Processing of Neurotrophins This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NGF processing This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Part of pro-beta-NGF is processed to mature beta-NGF This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> pro-beta-NGF homodimer Reactome DB_ID: 9766810 Golgi lumen GENE ONTOLOGY GO:0005796 Ngf NGF(19-241) P01139 Reactome DB_ID: 9766808 UniProt:P01139 Ngf Ngf Ngfb FUNCTION Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems (PubMed:20036257). Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades to regulate neuronal proliferation, differentiation and survival (PubMed:22649032). The immature NGF precursor (proNGF) functions as ligand for the heterodimeric receptor formed by SORCS2 and NGFR, and activates cellular signaling cascades that lead to inactivation of RAC1 and/or RAC2, reorganization of the actin cytoskeleton and neuronal growth cone collapse (PubMed:22155786). In contrast to mature NGF, the precursor form (proNGF) promotes neuronal apoptosis (in vitro) (PubMed:20036257). Inhibits metalloproteinase-dependent proteolysis of platelet glycoprotein VI (By similarity). Binds lysophosphatidylinositol and lysophosphatidylserine between the two chains of the homodimer (PubMed:22649032, PubMed:26144237). The lipid-bound form promotes histamine relase from mast cells, contrary to the lipid-free form (PubMed:22649032).SUBUNIT Homodimer (PubMed:1956407, PubMed:8201620, PubMed:20036257, PubMed:22649032, PubMed:26144237, PubMed:30061605). The homodimer interacts with a single NTRK1 chain (PubMed:22649032). The homodimer interacts with a single NGFR chain (By similarity). The NGF dimer interacts with a single SORCS2 chain (via extracellular domain) (PubMed:30061605). The NGF precursor (proNGF) binds to a receptor complex formed by SORT1 and NGFR, which leads to NGF endocytosis (PubMed:20036257). Both mature NGF and the immature NGF precursor (proNGF) interact with SORCS2 and with the heterodimer formed by SORCS2 and NGFR (via extracellular domains) (PubMed:22155786, PubMed:30061605). The NGF precursor (proNGF) has much higher affinity for SORCS2 than mature NGF (PubMed:24908487). The NGF precursor (proNGF) has much higher affinity for SORT1 than mature NGF (PubMed:20036257). Interacts with ADAM10 in a divalent cation-dependent manner (By similarity).TISSUE SPECIFICITY Detected in submaxillary gland (at protein level) (PubMed:1284621). Highly expressed in male submaxillary gland. Levels are much lower in female submaxillary gland (PubMed:6336309, PubMed:1284621).INDUCTION Expression oscillates in a circadian manner in the suprachiasmatic nucleus (SCN) of the brain.SIMILARITY Belongs to the NGF-beta family. Mus musculus NCBI Taxonomy 10090 UniProt P01139 19 EQUAL 241 EQUAL Reactome Database ID Release 78 9766808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766808 Reactome R-MMU-187036 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187036.1 Reactome http://www.reactome.org 2 Reactome Database ID Release 78 9766810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766810 Reactome R-MMU-187028 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187028.1 mature beta-NGF homodimer Reactome DB_ID: 9766814 Ngf NGF P01139 Reactome DB_ID: 9766812 122 EQUAL 241 EQUAL Reactome Database ID Release 78 9766812 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766812 Reactome R-MMU-166515 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166515.1 2 Reactome Database ID Release 78 9766814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766814 Reactome R-MMU-187017 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187017.1 ACTIVATION Subtilisin/kexin convertase (Calcium dependant) Reactome DB_ID: 9766827 Ca2+ Calcium calcium(2+) Reactome DB_ID: 167012 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 78 167012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167012 Reactome R-ALL-167012 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-167012.3 COMPOUND C00076 additional information MI MI:0361 1 Converted from EntitySet in Reactome Subtilisin/kexin-like convertase Reactome DB_ID: 9766825 Pcsk6 PCSK6 F6XJP7 Reactome DB_ID: 9766818 UniProt:F6XJP7 Pcsk6 UniProt F6XJP7 150 EQUAL 969 EQUAL Reactome Database ID Release 78 9766818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766818 Reactome R-MMU-3009047 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-3009047.1 Pcsk5 PCSK5(115-913) Q04592 Reactome DB_ID: 9766821 UniProt:Q04592 Pcsk5 Pcsk5 FUNCTION Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive and regulated secretory pathways. Plays an essential role in pregnancy establishment by proteolytic activation of a number of important factors such as BMP2, CALD1 and alpha-integrins. May be responsible for the maturation of gastrointestinal peptides. May be involved in the cellular proliferation of adrenal cortex via the activation of growth factors.TISSUE SPECIFICITY PC5A is expressed in most tissues but is most abundant in the intestine and adrenals. PC5B is expressed in the intestine, adrenals and lung but not in the brain.DEVELOPMENTAL STAGE Weakly expressed throughout the embryo, except in the developing nervous system, the ribs and the liver, but markedly up-regulated at discrete sites during development. At 6.5 dpc, prominent expression observed in differentiated decidua. At 7.5 dpc, intense expression in extraembryonic endoderm, amnion and nascent mesoderm. At 8.5 dpc, abundant expression in somites and yolk sac followed by a confinement to dermamyotome compartment. Between 9.5 dpc and 11.5 dpc, abundant expression in AER (thickened ectodermal cells of limb buds). At 12.5 dpc, expression in the limbs is confined to the condensing mesenchyme surrounding the cartilage. At this stage, strong expression also detected in vertebral and facial cartilage primordia and in the muscle of the tongue. At 16.5 dpc, abundant expression in epithelial cells of the intestinal villi. Isoform A is most abundant at all stages but significant levels of isoform B occur at 12.5 dpc.DOMAIN The propeptide domain acts as an intramolecular chaperone assisting the folding of the zymogen within the endoplasmic reticulum.DOMAIN AC 1 and AC 2 (clusters of acidic amino acids) contain sorting information. AC 1 directs TGN localization and interacts with the TGN sorting protein PACS-1.SIMILARITY Belongs to the peptidase S8 family. UniProt Q04592 115 EQUAL 913 EQUAL Reactome Database ID Release 78 9766821 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766821 Reactome R-MMU-166558 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166558.1 Furin FURIN P23188 Reactome DB_ID: 9766823 UniProt:P23188 Furin Furin Fur Pcsk3 FUNCTION Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif (By similarity). Mediates processing of TGFB1, an essential step in TGF-beta-1 activation (By similarity). Converts through proteolytic cleavage the non-functional Brain natriuretic factor prohormone into its active hormone BNP(1-45) (By similarity).ACTIVITY REGULATION Inhibited by the not secondly cleaved propeptide. Inhibited by m-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)-benzamidine (m-guanidinomethyl-Phac-RVR-Amb) and 4-guanidinomethyl-phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148). Inhibited by Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decanoyl-RVKR-CMK).SUBUNIT Interacts with FLNA (PubMed:9412467). Binds to PACS1 which mediates TGN localization and connection to clathrin adapters (By similarity).TISSUE SPECIFICITY Seems to be expressed ubiquitously.DOMAIN Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface.PTM The inhibition peptide, which plays the role of an intramolecular chaperone, is autocatalytically removed in the endoplasmic reticulum (ER) and remains non-covalently bound to furin as a potent autoinhibitor. Following transport to the trans Golgi, a second cleavage within the inhibition propeptide results in propeptide dissociation and furin activation.PTM Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms.SIMILARITY Belongs to the peptidase S8 family. Furin subfamily. UniProt P23188 108 EQUAL 794 EQUAL Reactome Database ID Release 78 9766823 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766823 Reactome R-MMU-448351 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-448351.1 Reactome Database ID Release 78 9766825 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766825 Reactome R-MMU-166569 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166569.1 1 Reactome Database ID Release 78 9766827 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766827 Reactome R-MMU-166611 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166611.1 GENE ONTOLOGY GO:0004252 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 9766828 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766828 Reactome Database ID Release 78 9766830 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766830 Reactome R-MMU-187020 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187020.1 The pro-neurotrophins are rapidly cleaved intra-cellularly by furin or the pro-protein convertases at a highly conserved site, to produce the mature protein of 12-14 kDa in size (mature NGF or beta-NGF: 12.5 kDa). Furin, PACE4 and PC7 belong to the constitutive secretory pathway; NEC1/PC1, NEC2/PC2, PC4 and PC5 are instead targeted to regulated secretory granules. Furin is expressed ubiquitously in all tissues, whereas NEC1 and NEC2 are the dominant pro-protein convertases in neurons. The mature neurotrophins can be stored within neurons and released extra-cellularly upon stimulation.<br>Cells, however, appear to have a limited capacity to process pro-neurotrophins, a capacity that may be exhausted when they are produced in excess (Matsumoto T et al, 2008). In this case, the proforms of NGF and BDNF are secreted and cleaved extracellularly by the serine protease plasmin and by selective matrix metalloproteinases (MMPs). The signalling capacities of pro-neurotrophins and mature neurotrophins are markedly different. The pro-neurotrophins are high affinity ligands for p75NTR and can induce p75NTR dependent apoptosis in cultured neurons with minimal activation of TRK receptor mediated differentiation or survival. The biological action of neurotrophins may thus be regulated by proteolytic cleavage, with proforms preferentially activating p75NTR to mediate apoptosis and mature forms activating TRK receptors to promote survival.<br>It is possible that pro-neurotrophins may somehow be released during development and eliminate neurons in a p75NTR dependent fashion. Substantial quantities of proNGF are found in the cerebrospinal fluid of adult rodents after brain injury, perhaps following NGF expression by inflammatory cells that may not efficiently process pro-neurotrophins. When proBDNF is added as recombinant protein, activation of p75NTR by proBDNF facilitates hippocampal long-term depression (LTD; Woo NH et al, 2005). However, it is unclear whether proBDNF plays any role in LTD under physiological conditions. 18204444 Pubmed 2008 Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF Matsumoto, T Rauskolb, S Polack, M Klose, J Kolbeck, R Korte, M Barde, YA Nat Neurosci 11:131-3 8615794 Pubmed 1996 Cellular processing of the nerve growth factor precursor by the mammalian pro-protein convertases Seidah, NG Benjannet, S Pareek, S Savaria, D Hamelin, J Goulet, B Laliberte, J Lazure, C Chretien, M Murphy, RA Biochem J 314:951-60 16025106 Pubmed 2005 Activation of p75NTR by proBDNF facilitates hippocampal long-term depression Woo, NH Teng, HK Siao, CJ Chiaruttini, C Pang, PT Milner, TA Hempstead, BL Lu, B Nat Neurosci 8:1069-77 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT Pro-beta-NGF and mature beta-NGF are secreted This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> pro-beta-NGF homodimer Reactome DB_ID: 9766834 extracellular region GENE ONTOLOGY GO:0005576 Ngf NGF(19-241) P01139 Reactome DB_ID: 9766832 19 EQUAL 241 EQUAL Reactome Database ID Release 78 9766832 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766832 Reactome R-MMU-187033 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187033.1 2 Reactome Database ID Release 78 9766834 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766834 Reactome R-MMU-187029 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187029.1 beta-NGF homodimer Reactome DB_ID: 198272 beta-NGF Reactome DB_ID: 181839 122 EQUAL 241 EQUAL Reactome Database ID Release 78 181839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181839 Reactome R-MMU-181839 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-181839.1 2 Reactome Database ID Release 78 198272 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198272 Reactome R-MMU-198272 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198272.1 Reactome Database ID Release 78 9766836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766836 Reactome R-MMU-187035 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187035.1 Both mature neurotrophin and pro-neurotrophin are released extracellularly and are biologically active. The precursor proNGF, instead of mNGF (mature NGF), is the molecular form preferentially released by neurons in an activity-dependent manner. Neurotrophins are secreted in low amounts from several tissues, mainly from target tissues of innervating neurons. In the nervous system, they are secreted by neurons, astrocytes and microglia. Neurotrophin secretion can be both constitutive and regulated. Constitutive release is observed in cells lacking a regulated pathway, and additional stimulus-dependent regulated secretion is evident in those cells where this route is available. Secretion is regulated by a number of stimuli, including neurotrophins themselves. In neurons, regulated secretion appears to be the prevalent pathway. NGF is secreted from the cell soma and the dendrites, while it is unclear whether it can also be secreted by axons. Constitutive secretion of NGF is observed only from the soma and the most proximal dendrites. Similar considerations hold for the other neurotrophins as well. 12787574 Pubmed 2003 Neurotrophin secretion: current facts and future prospects Lessmann, V Gottmann, K Malcangio, M Prog Neurobiol 69:341-74 Reactome Database ID Release 78 9861052 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861052 Reactome R-MMU-167060 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167060.1 GENE ONTOLOGY GO:0032455 gene ontology term for cellular process MI MI:0359 All neurotrophins (NTs) are generated as pre-pro-neurotrophin precursors. The signal peptide is cleaved off as NT is associated with the endoplasmic reticulum (ER). The resulting pro-NT can form a homodimer spontaneously which then transits to the Golgi apparatus and then onto the trans-Golgi network (TGN). Resident protein convertases (PCs) can cleave off the pro-sequence and mature NT is is targeted to constitutively released vesicles. The pro-NT form can also be released to the extracellular region. Reactome Database ID Release 78 9861054 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861054 Reactome R-MMU-9036866 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9036866.1 Neurotrophins function as ligands for receptor tyrosine kinases of the NTRK (TRK) family, as well as the death receptor NGFR (p75NTR). While all four neurotrophins, NGF, BDNF, NTF3 (NT-3) and NTF4 (NT-4, NT-5, NTF5) can bind to and activate NGFR, they show different specificity for NTRKs. NGF exclusively activates NTRK1 (TRKA). BDNF and NTF4 are high affinity ligands for NTRK2 (TRKB). NTF3 is a high affinity ligand for NTRK3 (TRKC) and a low affinity ligand for NTRK2. Neurotrophins play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. For review, please refer to Lessmann et al. 2003, Chao 2003, and Park and Poo 2013.<br>Human NGF, also knowns as the nerve growth factor, is encoded by a gene on chromosome 1, which produces a single transcript. Nascent NGF protein, pre-pro-NGF, is 241 amino acids long. As pre-pro-NGF enters the endoplasmic reticulum (ER), the signal peptide, consisting of eighteen amino acids at the N-terminus, is cleaved, producing pro-NGF. Two molecules of pro-NGF form homodimers in the ER. After transport of pro-NGF homodimers to the Golgi, 103 amino acids at the N-terminus of pro-NGF are cleaved, producing mature NGF homodimers. Both pro-NGF homodimers and mature NGF homodimers are secreted to the extracellular space. Mature NGF homodimers activate NTRK1 signaling, while NGFR signaling can be activated by both mature and pro-NGF homodimers. Secreted pro-NGF homodimers may be cleaved by extracellular matrix proteases to produce mature NGF homodimers. For review, please refer to Poo 2001, Lu et al. 2005, Skaper et al. 2012, Bradshaw et al. 2015.<br>Human BDNF, also known as brain-derived neurotrophic factor, is encoded by a gene on chromosome 11, which, through the use of 9 alternative promoters and alternative splicing, produces 17 protein-coding transcripts. Most BDNF transcripts result in the same pre-pro-BDNF protein of 247 amino acids, but alternative promoters and different 5' and 3’UTRs allow to fine-tune regulation of BDNF expression at different developmental stages and at different levels of neuronal activity. Similar to NGF, pre-pro-BDNF is processed by proteolytic cleavage in the ER to produce pro-BDNF homodimers. It is unclear whether proteolytic processing of pro-BDNF, to produce mature BDNF homodimers, occurs in the Golgi or in the secretory granules. Extracellular matrix proteases can also cleave secreted pro-BDNF to produce mature BDNF homodimers. Secreted mature BDNF homodimers can activate NTRK2 signaling, while secreted pro-BDNF homodimers can activate NGFR signaling. For review, please refer to Poo 2001, Lu et al. 2005, Skaper et al. 2012, Park and Poo 2013.<br>Human NTF4, also known as neurotrophin-4, is transcribed from a gene on chromosome 19. A single experimentally confirmed transcript produces a pre-pro-NTF4 protein of 210 amino acids. After proteolytic processing in the ER and Golgi, mature NTF4 homodimers are secreted and can activate NTRK2 signaling (Hibbert et al. 2003). For review, please refer to Poo 2001, Skaper et al. 2012.<br>Human NTF3, also known as neurotrophin-3, is transcribed from a gene on chromosome 12. Two NTF3 transcripts have been experimentally confirmed, but only the longer NTF3 splice variant of 270 amino acids has been studied. After proteolytic processing in the ER and Golgi, mature NTF3 homodimers are secreted and can activate NTRK3 signaling (Seidah et al. 1996, Farhadi et al. 2000). For review, please refer to Poo 2001, Skaper et al. 2012. 25491371 Pubmed 2015 NGF and ProNGF: Regulation of neuronal and neoplastic responses through receptor signaling Bradshaw, RA Pundavela, Jay Biarc, Jordane Chalkley, Robert J Burlingame, A L Hondermarck, Hubert Adv Biol Regul 58:16-27 12970359 Pubmed 2003 Neurotrophin-4, alone or heterodimerized with brain-derived neurotrophic factor, is sorted to the constitutive secretory pathway Hibbert, Andrew P Morris, Stephen J Seidah, Nabil G Murphy, Richard A J. Biol. Chem. 278:48129-36 11253356 Pubmed 2001 Neurotrophins as synaptic modulators Poo, M M Nat. Rev. Neurosci. 2:24-32 12671646 Pubmed 2003 Neurotrophins and their receptors: a convergence point for many signalling pathways Chao, MV Nat Rev Neurosci 4:299-309 22367796 Pubmed 2012 The neurotrophin family of neurotrophic factors: an overview Skaper, Stephen D Methods Mol. Biol. 846:1-12 16062169 Pubmed 2005 The yin and yang of neurotrophin action Lu, Bai Pang, Petti T Woo, Newton H Nat. Rev. Neurosci. 6:603-14 10818141 Pubmed 2000 Neurotrophin-3 sorts to the constitutive secretory pathway of hippocampal neurons and is diverted to the regulated secretory pathway by coexpression with brain-derived neurotrophic factor Farhadi, H F Mowla, S J Petrecca, K Morris, S J Seidah, N G Murphy, R A J. Neurosci. 20:4059-68 23254191 Pubmed 2013 Neurotrophin regulation of neural circuit development and function Park, Hyungju Poo, Mu-Ming Nat. Rev. Neurosci. 14:7-23 8603699 Pubmed 1996 Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases Seidah, N G Benjannet, S Pareek, S Chrétien, M Murphy, R A FEBS Lett. 379:247-50 Signaling by NTRK1 (TRKA) NGF signalling via TRKA from the plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Activation of TRKA receptors This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TRKA activation by NGF This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT beta-NGF dimer binds to TrkA receptor This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Ntrk1 NTRK1 Q3UFB7 Reactome DB_ID: 9763050 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:Q3UFB7 Ntrk1 Ntrk1 FUNCTION Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.ACTIVITY REGULATION The pro-survival signaling effect of NTRK1 in neurons requires its endocytosis into signaling early endosomes and its retrograde axonal transport. This is regulated by different proteins including CFL1, RAC1 and SORT1. NTF3 is unable to induce this signaling probably due to the lability of the NTF3-NTRK1 complex in endosomes. SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades. Regulated by NGFR.SUBUNIT Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Homodimerization is induced by binding of a NGF dimer (By similarity). Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a nerve growth factor (NGF)-dependent manner. Interacts with RAPGEF2; the interaction is strengthened after NGF stimulation. Interacts with SQSTM1; bridges NTRK1 to NGFR. Forms a ternary complex with NGFR and KIDINS220; this complex is affected by the expression levels of KIDINS220 and an increase in KIDINS220 expression leads to a decreased association of NGFR and NTRK1. Interacts (phosphorylated upon activation by NGF) with SHC1; mediates SHC1 phosphorylation and activation. Interacts (phosphorylated upon activation by NGF) with PLCG1; mediates PLCG1 phosphorylation and activation. Interacts (phosphorylated) with SH2B1 and SH2B2. Interacts with GRB2. Interacts with PIK3R1. Interacts with FRS2. Interacts with SORT1; may regulate NTRK1 anterograde axonal transport (By similarity). Interacts with SH2D1A; regulates NTRK1 (PubMed:16223723). Interacts with NRADD. Interacts with RAB7A. Interacts with PTPRS (By similarity). Interacts with USP36; USP36 does not deubiquitinate NTRK1 (By similarity). Interacts with GGA3 (By similarity).DEVELOPMENTAL STAGE First detected at 13.5 dpc, a time coinciding with the requirement of sympathetic neurons for NGF.INDUCTION Expression oscillates in a circadian manner in the suprachiasmatic nucleus (SCN) of the brain.DOMAIN The transmembrane domain mediates interaction with KIDINS220.DOMAIN The extracellular domain mediates interaction with NGFR.PTM Ligand-mediated autophosphorylation. Interaction with SQSTM1 is phosphotyrosine-dependent. Autophosphorylation at Tyr-499 mediates interaction and phosphorylation of SHC1.PTM N-glycosylated.PTM Ubiquitinated (PubMed:16113645). Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination by NEDD4L leads to degradation (By similarity). Ubiquitination regulates the internalization of the receptor (PubMed:16113645).DISRUPTION PHENOTYPE Mice die early after birth due to severe sensory and sympathetic neuropathies characterized by extensive neuronal cell loss in trigeminal, sympathetic and dorsal root ganglia, as well as a decrease in the cholinergic basal forebrain projections to the hippocampus and cortex. There are for instance 35% fewer cells by 17.5 dpc in the superior cervical ganglion, a major component of the sympathetic system.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily. UniProt Q3UFB7 33 EQUAL 796 EQUAL Reactome Database ID Release 78 9763050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9763050 Reactome R-MMU-3008784 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-3008784.1 beta-NGF dimer:TrkA receptor Reactome DB_ID: 9763053 1 1 Reactome Database ID Release 78 9763053 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9763053 Reactome R-MMU-166537 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166537.1 Reactome Database ID Release 78 9763059 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9763059 Reactome R-MMU-166542 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166542.1 Neurotrophin dimer binding to TRK receptors causes receptor dimerization. Although the dissociation constants of NGF for TRK and p75NTR are very similar, the binding kinetics are quite different: NGF associates with and dissociates from p75NTR much more rapidly than from TRKA. p75NTR regulates the affinity and specificity of TRK receptor activation by neurotrophins is regulated. Its presence is required to observe high affinity binding to TRK receptors, since it increases the rate of neurotrophin association with TRK proteins. The major ligand binding domain in TRK receptors is the membrane-proximal Ig-C2-like domain (named Ig2 domain or domain 5), although other regions in in the TRK extracellular domains are also important for ligand binding.<br>The N termini of neurotrophins are important in controlling binding specificity, and the structure of this region is reorganized upon binding to a TRK receptor. In some neurons, TRK receptors are localized to intracellular vesicles in the absence of signals. Electrical activity, cAMP, and Ca2+ stimulate TRK insertion into the cell surface by exocytosis of cytoplasmic membrane vesicles containing TRK. At axon terminals, TRK receptors undergo ligand-dependent endocytosis upon ligand binding. The internalized neurotrophin-TRK complex is then sorted and enters either recycling or retrograde transport pathways.<br> 1850549 Pubmed 1991 The trk proto-oncogene product: a signal transducing receptor for nerve growth factor Kaplan, DR Hempstead, BL Martin-Zanca, D Chao, MV Parada, LF Science 252:554-8 10490030 Pubmed 1999 Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor Wiesmann, C Ultsch, MH Bass, SH de Vos, AM Nature 401:184-8 1849459 Pubmed 1991 The trk proto-oncogene encodes a receptor for nerve growth factor Klein, R Jing, SQ Nanduri, V O'Rourke, E Barbacid, M Cell 65:189-97 LEFT-TO-RIGHT The bound receptor dimerizes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> beta-NGF dimer:TrkA receptor dimer Reactome DB_ID: 9763055 1 1 Reactome Database ID Release 78 9763055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9763055 Reactome R-MMU-166543 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166543.1 Reactome Database ID Release 78 9763057 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9763057 Reactome R-MMU-166538 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166538.1 The binding of neurotrotrophin to TrkA receptors induce their dimerization to form receptor homodimers. LEFT-TO-RIGHT Activated TrkA receptor internalizes to endosomes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Activated TrkA receptor complex Reactome DB_ID: 9764296 Q3UFB7 phospho-Ntrk1 p-5Y-NTRK1 Reactome DB_ID: 9764294 490 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 670 EQUAL 674 EQUAL 675 EQUAL 785 EQUAL 33 EQUAL 796 EQUAL Reactome Database ID Release 78 9764294 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764294 Reactome R-MMU-3009413 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-3009413.1 2 1 Reactome Database ID Release 78 9764296 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764296 Reactome R-MMU-166540 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166540.1 Activated TrkA receptor complex Reactome DB_ID: 9764663 endosome membrane GENE ONTOLOGY GO:0010008 beta-NGF homodimer Reactome DB_ID: 9764661 cytosol GENE ONTOLOGY GO:0005829 Ngf NGF P01139 Reactome DB_ID: 9764659 122 EQUAL 241 EQUAL Reactome Database ID Release 78 9764659 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764659 Reactome R-MMU-190059 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190059.1 2 Reactome Database ID Release 78 9764661 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764661 Reactome R-MMU-190067 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190067.1 1 Q3UFB7 phospho-Ntrk1 p-5Y-NTRK1-1 Reactome DB_ID: 9764657 33 EQUAL 796 EQUAL Reactome Database ID Release 78 9764657 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764657 Reactome R-MMU-190064 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190064.1 2 Reactome Database ID Release 78 9764663 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764663 Reactome R-MMU-190083 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190083.1 Reactome Database ID Release 78 9767174 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9767174 Reactome R-MMU-190065 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190065.1 TRKA at the plasma membrane typically results in rapid endocytosis and subsequent passage of the receptors through a network of endosomal compartments (Harrington et al, 2011; Wu et al, 2001). 21816277 Pubmed 2011 Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival Harrington, Anthony W St Hillaire, Coryse Zweifel, Larry S Glebova, Natalia O Philippidou, Polyxeni Halegoua, Simon Ginty, David D Cell 146:421-34 11466412 Pubmed 2001 Nerve growth factor activates persistent Rap1 signaling in endosomes Lai, CF Mobley, WC J Neurosci 21:5406-16 Reactome Database ID Release 78 9860796 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860796 Reactome R-MMU-187042 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187042.1 GENE ONTOLOGY GO:0048011 Neurotrophin functions are mediated by binding of the secreted neurotrophin homodimers to their common neurotrophin receptor p75NTR, and to their cognate tropomyosin related kinase (TRK) receptor. NGF binds to TRKA, BDNF and NT4 bind to TRKB, NT3 binds to TRKC. A tri-molecular signalling complex (NGF-p75NTR-TRKA) might also be possible. 1844238 Pubmed 1991 The trk family of oncogenes and neurotrophin receptors Lamballe, F Klein, R Barbacid, M Princess Takamatsu Symp 22:153-70 1315923 Pubmed 1992 The nerve growth factor receptor: a multicomponent system that mediates the actions of the neurotrophin family of proteins Barker, PA Murphy, RA Mol Cell Biochem 110:1-15 Reactome Database ID Release 78 9860798 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860798 Reactome R-MMU-187015 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187015.1 GENE ONTOLOGY GO:0007169 Trk receptors can either be activated by neurotrophins or by two G-protein-coupled receptors (GPCRs) although the biological relevance of GPCRs remains to be shown. 16939974 Pubmed 2006 Neurotrophin-regulated signalling pathways Reichardt, LF Philos Trans R Soc Lond B Biol Sci 361:1545-64 Signalling to ERKs This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Signalling to RAS This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT GRB2-1:SOS1 binds p-Y-SHC This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome p-Y-SHC Reactome DB_ID: 9828094 P98083 phospho-Shc1 p-Y-SHC1 Reactome DB_ID: 9785928 UniProt:P98083 Shc1 Shc1 Shc ShcA FUNCTION Signaling adapter that couples activated growth factor receptors to signaling pathways. Participates in signaling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis (By similarity). Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Isoform p47Shc and isoform p52Shc, once phosphorylated, couple activated receptor kinases to Ras via the recruitment of the GRB2/SOS complex and are implicated in the cytoplasmic propagation of mitogenic signals. Isoform p47Shc and isoform p52 may thus function as initiators of the Ras signaling cascade in various non-neuronal systems. Isoform p66Shc does not mediate Ras activation, but is involved in signal transduction pathways that regulate the cellular response to oxidative stress and life span. Isoform p66Shc acts as a downstream target of the tumor suppressor p53 and is indispensable for the ability of stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release and apoptosis. The expression of isoform p66Shc has been correlated with life span.SUBUNIT Interacts with CPNE3; this interaction may mediate the binding of CPNE3 with ERBB2 (By similarity). Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR in vitro via the PID domain. Once activated, binds to GRB2. Interacts with tyrosine-phosphorylated DDR2 and CD3T. Interacts with the N-terminal region of APS. Interacts with GRB7 and KIT (By similarity). Interacts with PTK2/FAK1 (By similarity). Interacts with phosphorylated LRP1 and IRS4. Interacts with FLT4 (tyrosine-phosphorylated) (By similarity). Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with ERBB4 (By similarity). Interacts with TEK/TIE2 (tyrosine-phosphorylated) (By similarity). Interacts with ALK, GAB2, TRIM31, INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with PTPN6/SHP (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Interacts with EPHB1 and GRB2; activates the MAPK/ERK cascade to regulate cell migration. Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a phosphotyrosine-dependent manner. Interacts with CEACAM1; this interaction is CEACAM1-phosphorylation-dependent and mediates interaction with EGFR or INSR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (By similarity) (PubMed:15467833). Interacts (via PID domain) with PEAK1 (when phosphorylated at 'Tyr-1177') (By similarity). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (By similarity).TISSUE SPECIFICITY Widely expressed. Expressed in neural stem cells but absent in mature neurons.DOMAIN In response to a variety of growth factors, isoform p47Shc and isoform p52 bind to phosphorylated receptors through their phosphotyrosine binding (PID) and/or SH2 domains. The PID and SH2 domains bind to specific phosphorylated tyrosine residues in the Asn-Pro-Xaa-Tyr(P) motif. Isoform p47Shc and isoform p52Shc are in turn phosphorylated on three tyrosine residues within the extended proline-rich domain. These phosphotyrosines act as docking site for GRB2 and thereby are involved in Ras activation.PTM Phosphorylated in response to FLT4 signaling (By similarity). Tyrosine phosphorylated by ligand-activated PDGFRB (By similarity). May be tyrosine phosphorylated by activated PTK2/FAK1 (By similarity). Tyrosine phosphorylated by TEK/TIE2 (By similarity). Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity). Dephosphorylation by PTPN2 may regulate interaction with GRB2 (By similarity). Phosphorylated by activated epidermal growth factor receptor. Phosphorylated in response to KIT signaling. Isoform p47Shc and isoform p52Shc are phosphorylated on tyrosine residues of the Pro-rich domain. Isoform p66Shc is phosphorylated on Ser-36 by PRKCB upon treatment with insulin, hydrogen peroxide or irradiation with ultraviolet light. FLT3 signaling promotes tyrosine phosphorylation of isoform p47Shc and isoform p52Shc. Also tyrosine phosphorylated by ligand-activated ALK. UniProt P98083 1 EQUAL 583 EQUAL Reactome Database ID Release 78 9785928 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9785928 Reactome R-MMU-162568 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-162568.1 Q8BMC3 phospho-Shc2 p-Y-SHC2 Reactome DB_ID: 9828087 UniProt:Q8BMC3 Shc2 UniProt Q8BMC3 1 EQUAL 582 EQUAL Reactome Database ID Release 78 9828087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828087 Reactome R-MMU-167051 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167051.1 Q61120 phospho-Shc3 p-Y-SHC3 Reactome DB_ID: 9828092 UniProt:Q61120 Shc3 UniProt Q61120 1 EQUAL 594 EQUAL Reactome Database ID Release 78 9828092 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828092 Reactome R-MMU-3009043 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-3009043.1 Reactome Database ID Release 78 9828094 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828094 Reactome R-MMU-167016 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167016.1 GRB2-1:SOS1 Reactome DB_ID: 9756228 Sos1 SOS1 Q62245 Reactome DB_ID: 9756226 UniProt:Q62245 Sos1 Sos1 FUNCTION Promotes the exchange of Ras-bound GDP by GTP. Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (By similarity). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity (PubMed:10499589, PubMed:11524436).SUBUNIT Interacts (via C-terminus) with GRB2 (via SH3 domain). Forms a complex with phosphorylated MUC1 and GRB2 (via its SH3 domains). Interacts with phosphorylated LAT2. Interacts with NCK1 and NCK2 (By similarity). Part of a complex consisting of ABI1, EPS8 and SOS1 (PubMed:10499589, PubMed:11524436). Interacts (Ser-1120 and Ser-1147 phosphorylated form) with YWHAB and YWHAE (By similarity).TISSUE SPECIFICITY Expressed in most embryonic and adult tissues.PTM Phosphorylation at Ser-1120 and Ser-1147 by RPS6KA3 create YWHAB and YWHAE binding sites and which contribute to the negative regulation of EGF-induced MAPK1/3 phosphorylation. UniProt Q62245 1 EQUAL 1333 EQUAL Reactome Database ID Release 78 9756226 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756226 Reactome R-MMU-64847 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-64847.1 1 Grb2 GRB2-1 Q60631 Reactome DB_ID: 9756223 UniProt:Q60631 Grb2 Grb2 FUNCTION Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.SUBUNIT Associates (via SH2 domain) with activated EGF and PDGF receptors (tyrosine phosphorylated) (By similarity). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect (PubMed:8943348). Interacts with IRS4 (when Tyr-phosphorylated) (PubMed:11113178). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, IRS1, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains (By similarity). It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1 (By similarity). Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1 (By similarity). Interacts with phosphorylated MET (By similarity). Interacts with phosphorylated TOM1L1 (PubMed:11711534). Interacts with the phosphorylated C-terminus of SH2B2 (By similarity). Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation (By similarity) (PubMed:16249387, PubMed:14610044, PubMed:15477350, PubMed:15477348, PubMed:22561606). Interacts with NISCH, PTPNS1 and REPS2 (By similarity). Interacts with syntrophin SNTA1 (PubMed:11551227). Interacts (via SH3 domains) with REPS1 (PubMed:9395447). Interacts (via SH3 domains) with PIK3C2B (By similarity). Interacts with CBL and CBLB (By similarity). Interacts with AJUBA and CLNK (PubMed:10330178, PubMed:11463797). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (PubMed:10521483). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2 (By similarity). Interacts with PTPN11 (PubMed:8943348). Interacts with PRNP (PubMed:11571277). Interacts with RALGPS1 (By similarity). Interacts also with HCST (PubMed:16582911). Interacts with KDR (PubMed:16966330). Interacts with FLT1 (tyrosine-phosphorylated) (PubMed:9722576). Interacts with GAPT and PTPRE (By similarity). Interacts (via SH2 domain) with KIF26A (By similarity). Interacts (via SH3 2) with GAB2 (PubMed:10068651). Interacts with ADAM15 (By similarity). Interacts with THEMIS2 (PubMed:20644716). Interacts (via SH2 domain) with AXL (phosphorylated) (By similarity). Interacts (via SH2 domain) with KIT (phosphorylated) (PubMed:10377264). Interacts with PTPRJ and BCR (By similarity). Interacts with PTPN23 (By similarity). Interacts with FLT4 (tyrosine phosphorylated) (By similarity). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Part of a complex including TNK2, GRB2 and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2 (By similarity). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:9312046). Interacts with ERBB4 (By similarity). Interacts with NTRK1 (phosphorylated upon ligand-binding) (By similarity). Interacts with PTK2/FAK1 (tyrosine phosphorylated) (PubMed:7997267). Interacts with PTK2B/PYK2 (tyrosine phosphorylated) (By similarity). Interacts (via SH2-domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-58' (PubMed:21930792, PubMed:28098138, PubMed:28290451). Interacts (via SH3 domains) with GAREM1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation (By similarity). Interacts with DAB2 (PubMed:9569023). Interacts with TESPA1 (By similarity). Interacts with THEMIS (PubMed:19597498, PubMed:19597497, PubMed:19805304, PubMed:22561606). Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1 (PubMed:22561606). Interacts with CD28 (By similarity). Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA (PubMed:21543326). Interacts with ASAP3 (phosphorylated form) (By similarity). Interacts (via SH2 domain) with PTPRH (phosphorylated form) (PubMed:20398064). Interacts with PTPRO (phosphorylated form) (PubMed:20398064). Interacts with PTPRB (phosphorylated form) (PubMed:20398064). Interacts (via SH3 domain 2) with PRR14 (via proline-rich region) (By similarity). Interacts with DENND2B (By similarity). Interacts with SPRY2 (By similarity). Interacts with LRRC8A (PubMed:32930093).TISSUE SPECIFICITY Expressed in macrophages.DOMAIN The SH3 domains mediate interaction with RALGPS1 and SHB.SIMILARITY Belongs to the GRB2/sem-5/DRK family. UniProt Q60631 1 EQUAL 217 EQUAL Reactome Database ID Release 78 9756223 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756223 Reactome R-MMU-74686 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-74686.1 1 Reactome Database ID Release 78 9756228 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756228 Reactome R-MMU-109797 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109797.1 GRB2-1:SOS1:p-Y-SHC Reactome DB_ID: 9828096 1 1 Reactome Database ID Release 78 9828096 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828096 Reactome R-MMU-5685367 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5685367.1 Reactome Database ID Release 78 9829512 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829512 Reactome R-MMU-5685366 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5685366.1 Tyrosine-phosphorylated SHC1 recruits the SH2 domain of the adaptor protein GRB2, which is complexed with SOS1, an exchange factor for p21 Ras and Rac. GRB2 binds SOS1 through its SH3 domain. This domain can associate with other intracellular targets, including GAB1. ERK and Rsk mediated phosphorylation results in dissociation of the SOS1:GRB2 complex. This may explain why ERK activation through SHC and GRB2:SOS1 is transient. Inactive p21 Ras-GDP is found anchored to the plasma membrane by a farnesyl residue. As SHC is phosphorylated by the the stimulated receptor near to the plasma membrane, the GRB2:SOS1:SHC interaction brings SOS1 into close proximity to p21 Ras. 8810325 Pubmed 1996 Interactions between Src homology SH2/SH3 adapter proteins and the guanylnucleotide exchange factor SOS are differentially regulated by insulin and epidermal growth factor. Okada, S Pessin, JE J Biol Chem 271:25533-8 p38MAPK events This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Ral-GDS binds to Ras-GTP This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Ralgds RALGDS Q03385 Reactome DB_ID: 9764710 UniProt:Q03385 Ralgds UniProt Q03385 1 EQUAL 914 EQUAL Reactome Database ID Release 78 9764710 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764710 Reactome R-MMU-171001 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-171001.1 p21 RAS:GTP Reactome DB_ID: 9764706 GTP Guanosine 5'-triphosphate GTP)(4-) Reactome DB_ID: 29438 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI CHEBI:37565 Reactome Database ID Release 78 29438 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29438 Reactome R-ALL-29438 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29438.4 COMPOUND C00044 1 Converted from EntitySet in Reactome mature p21 RAS Reactome DB_ID: 9764704 Kras S-Farn-Me-PalmS KRAS4A P32883 Reactome DB_ID: 9764689 UniProt:P32883 Kras Kras Kras2 FUNCTION Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (By similarity). Plays an important role in the regulation of cell proliferation (PubMed:6474169, PubMed:1352876). Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner (By similarity).ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP). Interaction with SOS1 promotes exchange of bound GDP by GTP.SUBUNIT Interacts with PHLPP. Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts (when farnesylated) with PDE6D; this promotes dissociation from the cell membrane. Interacts with SOS1 (By similarity). Interacts (when farnesylated) with GPR31 (By similarity).PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.MISCELLANEOUS This gene is amplified in the mouse adrenal tumor Y1 cells, and is also directly linked to lung tumor susceptibility.SIMILARITY Belongs to the small GTPase superfamily. Ras family. UniProt P32883 186 EQUAL S-farnesyl-L-cysteine methyl ester MOD MOD:01116 179 EQUAL S-palmitoyl-L-cysteine MOD MOD:00115 1 EQUAL 186 EQUAL Reactome Database ID Release 78 9764689 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764689 Reactome R-MMU-9647915 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9647915.1 Nras S-Farn-Me PalmS NRAS P08556 Reactome DB_ID: 9764694 UniProt:P08556 Nras Nras FUNCTION Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).SUBUNIT Interacts (active GTP-bound form preferentially) with RGS14. Interacts (active GTP-bound form) with RASSF7 (By similarity).PTM Palmitoylated by the ZDHHC9-GOLGA7 complex. Depalmitoylated by ABHD17A, ABHD17B and ABHD17C. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi.PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.PTM Phosphorylation at Ser-89 by STK19 enhances NRAS-association with its downstream effectors.SIMILARITY Belongs to the small GTPase superfamily. Ras family. UniProt P08556 186 EQUAL 181 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 78 9764694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764694 Reactome R-MMU-9647910 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9647910.1 Hras S-Farn-Me-2xPalmS HRAS Q61411 Reactome DB_ID: 9764700 UniProt:Q61411 Hras Hras Hras1 FUNCTION Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).SUBUNIT Forms a signaling complex with RASGRP1 and DGKZ (By similarity). In its GTP-bound form interacts with PLCE1 (By similarity). Interacts with TBC1D10C and RASSF5 (By similarity). Interacts with PDE6D (By similarity). Interacts with IKZF3 (By similarity). Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14 (By similarity). Interacts (active GTP-bound form) with RGS14 (via RBD 1 domain) (By similarity). Interacts with RACK1 (By similarity). Interacts with RAPGEF2 (By similarity). Interacts with RGL3 (PubMed:10869344). Interacts with HSPD1 (PubMed:1347942). Interacts with PIK3CG; the interaction is required for membrane recruitment and beta-gamma G protein dimer-dependent activation of the PI3K gamma complex PIK3CG:PIK3R6 (PubMed:19906996). Interacts (in GTP-bound form) with Oog1 (PubMed:16580637).PTM Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi.PTM S-nitrosylated; critical for redox regulation. Important for stimulating guanine nucleotide exchange. No structural perturbation on nitrosylation.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation.PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.SIMILARITY Belongs to the small GTPase superfamily. Ras family. UniProt Q61411 186 EQUAL 181 EQUAL 184 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 78 9764700 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764700 Reactome R-MMU-9647912 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9647912.1 Reactome Database ID Release 78 9764704 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764704 Reactome R-MMU-9649715 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9649715.1 1 Reactome Database ID Release 78 9764706 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764706 Reactome R-MMU-109783 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109783.1 Ras-GTP:RalGDS complex Reactome DB_ID: 9764712 1 1 Reactome Database ID Release 78 9764712 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764712 Reactome R-MMU-171020 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-171020.1 Reactome Database ID Release 78 9764714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764714 Reactome R-MMU-170986 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-170986.1 Besides the RAF kinase, RAS can activate several ral guanine nucleotide dissociation stimulators (RALGDSs). Binding of RALGDS with RAS competes with RAF binding to RAS. 7972015 Pubmed 1994 Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator Hofer, F Fields, S Schneider, C Martin, GS Proc Natl Acad Sci U S A 91:11089-93 LEFT-TO-RIGHT 2.7.11 p38 MAPK phosphorylates MAPKAPK2, MAPKAPK3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 78 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 2 Converted from EntitySet in Reactome MAPKAP kinase Reactome DB_ID: 9766886 P49138 Mapkapk2 MAPKAPK2 Reactome DB_ID: 9766880 UniProt:P49138 Mapkapk2 UniProt P49138 1 EQUAL 400 EQUAL Reactome Database ID Release 78 9766880 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766880 Reactome R-MMU-187743 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187743.1 Q3UMW7 Mapkapk3 MAPKAPK3 Reactome DB_ID: 9766884 UniProt:Q3UMW7 Mapkapk3 UniProt Q3UMW7 1 EQUAL 382 EQUAL Reactome Database ID Release 78 9766884 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766884 Reactome R-MMU-187764 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187764.1 Reactome Database ID Release 78 9766886 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766886 Reactome R-MMU-187699 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187699.1 Converted from EntitySet in Reactome Active MAPKAP kinase p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 Reactome DB_ID: 9766897 P49138 phospho-Mapkapk2 p-S272,T222,T334-MAPKAPK2 Reactome DB_ID: 9766891 222 EQUAL O-phospho-L-threonine MOD MOD:00047 272 EQUAL O-phospho-L-serine MOD MOD:00046 334 EQUAL 1 EQUAL 400 EQUAL Reactome Database ID Release 78 9766891 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766891 Reactome R-MMU-187760 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187760.1 Q3UMW7 phospho-Mapkapk3 p-S,2T-MAPKAPK3 Reactome DB_ID: 9766895 1 EQUAL 382 EQUAL Reactome Database ID Release 78 9766895 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766895 Reactome R-MMU-187723 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187723.1 Reactome Database ID Release 78 9766897 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766897 Reactome R-MMU-187726 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187726.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 78 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 2 ACTIVATION Phospho-MAP kinase p38 (Mg2+ cofactor) Reactome DB_ID: 9766899 Mg2+ Magnesium magnesium(2+) Mg++ Reactome DB_ID: 29926 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI CHEBI:18420 Reactome Database ID Release 78 29926 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29926 Reactome R-ALL-29926 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29926.5 COMPOUND C00305 1 Converted from EntitySet in Reactome phospho-MAPK p38 alpha/beta Reactome DB_ID: 448863 phospho-MAP kinase p38 alpha Reactome DB_ID: 448842 UniProt:P47811 Mapk14 Mapk14 Crk1 Csbp1 Csbp2 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Phosphorylates S100A9 at 'Thr-113' (By similarity).ACTIVITY REGULATION Activated by cell stresses such as DNA damage, heat shock, osmotic shock, anisomycin and sodium arsenite, as well as pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) and interleukin-1. Activation occurs through dual phosphorylation of Thr-180 and Tyr-182 by either of two dual specificity kinases, MAP2K3/MKK3 or MAP2K6/MKK6, and potentially also MAP2K4/MKK4, as well as by TAB1-mediated autophosphorylation. MAPK14 phosphorylated on both Thr-180 and Tyr-182 is 10-20-fold more active than MAPK14 phosphorylated only on Thr-180, whereas MAPK14 phosphorylated on Tyr-182 alone is inactive. whereas Thr-180 is necessary for catalysis, Tyr-182 may be required for auto-activation and substrate recognition. Phosphorylated at Tyr-323 by ZAP70 in an alternative activation pathway in response to TCR signaling in T-cells. This alternative pathway is inhibited by GADD45A. Inhibited by dual specificity phosphatases, such as DUSP1, DUSP10, and DUSP16. Specifically inhibited by the binding of pyridinyl-imidazole compounds, which are cytokine-suppressive anti-inflammatory drugs (CSAID). SB203580 is an inhibitor of MAPK14.SUBUNIT Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (By similarity). Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR (By similarity). This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation (By similarity). Interacts with SPAG9 and GADD45A (By similarity). Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B. Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14 and may regulate its dephosphorylation (By similarity).TISSUE SPECIFICITY Macrophages, monocytes, T- and B-lymphocytes. Isoform 2 is specifically expressed in kidney and liver.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory cytokines, environmental stress or growth factors, which activates the enzyme. Dual phosphorylation can also be mediated by TAB1-mediated autophosphorylation. TCR engagement in T-cells also leads to Tyr-323 phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1, DUSP10 and DUSP16. PPM1D also mediates dephosphorylation and inactivation of MAPK14 (By similarity).PTM Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity. Lys-53 and Lys-152 are deacetylated by HDAC3 (By similarity).PTM Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway (By similarity).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt P47811 180 EQUAL 182 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 78 448842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=448842 Reactome R-MMU-448842 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-448842.1 phospho-MAP kinase p38 beta Reactome DB_ID: 448825 UniProt:Q9WUI1 Mapk11 Mapk11 Prkm11 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK11 functions are mostly redundant with those of MAPK14. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Additional examples of p38 MAPK substrates are the FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment.ACTIVITY REGULATION Activated by phosphorylation on threonine and tyrosine by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 induced by environmental stress. HDAC3 interacts directly and selectively with MAPK11 to repress ATF2 transcriptional activity, and regulate TNF gene expression in LPS-stimulated cells. Inhibited by SB203580 and pyridinyl-imidazole related compounds.SUBUNIT Interacts with HDAC3 and DUSP16.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-180 and Tyr-182 by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6, which activates the enzyme.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt Q9WUI1 180 EQUAL 182 EQUAL 1 EQUAL 364 EQUAL Reactome Database ID Release 78 448825 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=448825 Reactome R-MMU-448825 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-448825.1 Reactome Database ID Release 78 448863 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=448863 Reactome R-MMU-448863 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-448863.1 1 Reactome Database ID Release 78 9766899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766899 Reactome R-MMU-170993 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-170993.1 GENE ONTOLOGY GO:0004674 Reactome Database ID Release 78 9766900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766900 Reactome Database ID Release 78 9766902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766902 Reactome R-MMU-187688 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187688.1 Activated p38 MAPK is known to activate the Ser/Thr protein kinase MAP kinase-activated protein kinase 2 (MAPK2/MAPKAPK2) and a closely related kinase, MAPKAP kinase 3. MAPK2 is phosphorylated on T222, S272, and T334 (Ben-Levy et al. 1995). MAPK3 shows 75% sequence identity to MAPK2 and, like MAPK2, is phosphorylated by p38 but the exact phosphorylation sites are not determined. According to some authors, NGF does not induce any significant activation of MAPKAPK2 activity in PC12 cells. Potential p38 signaling effectors include transcription factors, such as cAMP-response element-binding protein and MEF2, cytoskeleton modulators, and a number of protein kinases. After activation, MAPKAP kinase 2 and 3 move to the nucleus. 8846784 Pubmed 1995 Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2 Ben-Levy, R Leighton, IA Doza, YN Attwood, P Morrice, N Marshall, CJ Cohen, P EMBO J 14:5920-30 Reactome Database ID Release 78 9860922 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860922 Reactome R-MMU-171007 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-171007.1 NGF induces sustained activation of p38, a member of the MAPK family (Morooka T, Nishida E, 1998). Both p38 and the ERKs appear to be involved in neurite outgrowth and differentiation caused by NGF in PC12 cells. As a matter of fact, PC12 cell differentiation appears to involve activation of both ERK/MAPK and p38. Both ERK/MAPK and p38 pathways contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes (Xing J, 1998). p38 activation by NGF may occur by at least two mechanisms, involving SRC or MEK kinases. 9528766 Pubmed 1998 Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation Xing, J Kornhauser, JM Xia, Z Thiele, EA Greenberg, ME Mol Cell Biol 18:1946-55 9733710 Pubmed 1998 Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells Morooka, T Nishida, E J Biol Chem 273:24285-8 9297626 Pubmed 1997 Ras effectors and their role in mitogenesis and oncogenesis Joneson, T Bar-Sagi, Dafna J Mol Med 75:587-93 Reactome Database ID Release 78 9860924 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860924 Reactome R-MMU-167044 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167044.1 GENE ONTOLOGY GO:0007265 Signalling through Shc adaptor proteins appears to be identical for both NGF and EGF. It leads to a fast, but transient, MAPK/ERK activation, which is insufficient to explain the prolonged activation of MAPK found in NGF-treated cells. 11520933 Pubmed 2001 Nerve growth factor signaling, neuroprotection, and neural repair Sofroniew, MV Howe, CL Mobley, WC Annu Rev Neurosci 24:1217-81 Prolonged ERK activation events This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Frs2-mediated activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT FRS2 binds to active TrkA receptor This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Frs2 Reactome DB_ID: 443125 UniProt:Q8C180 Frs2 Frs2 Frs2a FUNCTION Adapter protein that links activated FGR and NGF receptors to downstream signaling pathways. Plays an important role in the activation of MAP kinases and in the phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, in response to ligand-mediated activation of FGFR1. Modulates signaling via SHC1 by competing for a common binding site on NTRK1.SUBUNIT Part of a complex containing FRS2, GRB2, GAB1, PIK3R1 and SOS1. Part of a complex containing GRB2 and CBL. Binds ALK, CKS2, FGFR1, RET, MAPK1/ERK2, MAPK3/ERK1 and SRC. The tyrosine-phosphorylated protein binds the SH2 domains of GRB2 and PTPN11. Interacts with NTRK1, NTRK2 and NTRK3 (phosphorylated upon ligand-binding) (By similarity). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN.TISSUE SPECIFICITY Ubiquitous. Expression is highest in brain, kidney, lung and testis.PTM Phosphorylated on tyrosine residues upon stimulation by FGF2 or NGFB. Phosphorylated by ULK2 (in vitro). Phosphorylated on tyrosine residues by activated ALK and FGFR1. Phosphorylated on tyrosine residues upon activation of FGFR2 and FGFR3. Phosphorylated on threonine residues by MAP kinases; this inhibits tyrosine phosphorylation, and thereby down-regulates FRS2-mediated activation of MAP kinases.PTM Ubiquitinated when tyrosine phosphorylated and in a complex with GRB2. The unphosphorylated form is not subject to ubiquitination. UniProt Q8C180 2 EQUAL 508 EQUAL Reactome Database ID Release 78 443125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=443125 Reactome R-MMU-443125 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-443125.1 Active TrkA receptor:FRS2 complex Reactome DB_ID: 9764665 1 1 Reactome Database ID Release 78 9764665 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764665 Reactome R-MMU-190068 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190068.1 Reactome Database ID Release 78 9764667 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764667 Reactome R-MMU-170964 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-170964.1 FRS2 binds to TRKA through the same motif (NPXY) around the TRKA phospho-tyrosine residue Y496 to which SHC proteins bind. The competition between SHC proteins and FRS2 for binding to NGF-activated TRKA may provide a novel mechanism by which proliferation and differentiation may be regulated in response to neurotrophin stimulation. Tyrosine phosphorylation of FRS2 occurs within 2 min of NGF stimulation. 10629055 Pubmed 2000 FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors Ong, SH Guy, GR Hadari, YR Laks, S Gotoh, N Schlessinger, J Lax, I Mol Cell Biol 20:979-89 LEFT-TO-RIGHT 2.7.11 FRS2 is phosphorylated by active TrkA receptor This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 6 Active TrkA receptor:p-FRS2 complex Reactome DB_ID: 9764671 1 Q8C180 phospho-Frs2 p-6Y-FRS2 Reactome DB_ID: 9764669 436 EQUAL 196 EQUAL 306 EQUAL 349 EQUAL 392 EQUAL 471 EQUAL 2 EQUAL 508 EQUAL Reactome Database ID Release 78 9764669 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764669 Reactome R-MMU-190355 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190355.1 1 Reactome Database ID Release 78 9764671 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764671 Reactome R-MMU-190073 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190073.1 6 ACTIVATION Reactome Database ID Release 78 9764672 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764672 Reactome Database ID Release 78 9764674 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764674 Reactome R-MMU-170977 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-170977.1 Activated TrkA induces the tyrosine phosphorylation of the lipid-anchored docking protein, FRS2. FRS2 is an adapter protein that links NGF receptors to downstream signaling pathways. It is involved in the activation of MAP kinases. 9182757 Pubmed 1997 A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway Kouhara, H Hadari, YR Spivak-Kroizman, T Schilling, J Bar-Sagi, Dafna Lax, I Schlessinger, J Cell 89:693-702 LEFT-TO-RIGHT p-FRS2:CRKL binds C3G This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Active TrkA receptor:p-FRS2:CRKL complex Reactome DB_ID: 9764677 1 1 Crkl Crk-like protein CRKL_MOUSE Reactome DB_ID: 9027209 UniProt:P47941 Crkl Crkl Crkol FUNCTION May mediate the transduction of intracellular signals.SUBUNIT Interacts with DOCK2 and EPOR. Interacts with phosphorylated CBLB and IRS4 (By similarity). Interacts with INPP5D/SHIP1.PTM Phosphorylated on tyrosine. Phosphorylation is prominent during early development, but decreases at later embryonic stages and in newborn mice.SIMILARITY Belongs to the CRK family. UniProt P47941 1 EQUAL 303 EQUAL Reactome Database ID Release 78 9027209 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9027209 Reactome R-MMU-9027209 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9027209.1 1 Reactome Database ID Release 78 9764677 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764677 Reactome R-MMU-190081 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190081.1 Q3UHC1 Rapgef1 RAPGEF1 Reactome DB_ID: 9764680 UniProt:Q3UHC1 Rapgef1 Rapgef1 UniProt Q3UHC1 1 EQUAL 1077 EQUAL Reactome Database ID Release 78 9764680 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764680 Reactome R-MMU-913472 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-913472.1 Active TrkA receptor:p-FRS2:CRKL:RAPGEF1 Reactome DB_ID: 9764682 1 1 Reactome Database ID Release 78 9764682 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764682 Reactome R-MMU-190070 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190070.1 Reactome Database ID Release 78 9764684 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764684 Reactome R-MMU-170978 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-170978.1 Rap guanine nucleotide exchange factor 1 (RAPGEF1, C3G) is a guanine nucleotide exchange factor for Rap1, which is recruited by Crk adaptor proteins (Knudsen et al. 1994; York, 1998). 9560161 Pubmed 1998 Rap1 mediates sustained MAP kinase activation induced by nerve growth factor York, Randall D Yao, Hong Dillon, Tara Ellig, Cindy L Eckert, Stephani P McCleskey, Edwin W Stork, PJ Nature 392:622-6 7806500 Pubmed 1994 Four proline-rich sequences of the guanine-nucleotide exchange factor C3G bind with unique specificity to the first Src homology 3 domain of Crk Knudsen, BS Feller, SM Hanafusa, H J Biol Chem 269:32781-7 LEFT-TO-RIGHT 2.7.11 BRAF autophosphorylates downstream of RAP1 and NGF This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> RAP1:GTP:B-Raf complex Reactome DB_ID: 9856751 Rap1a RAP1A P62835 Reactome DB_ID: 9856725 UniProt:P62835 Rap1a UniProt P62835 1 EQUAL 181 EQUAL Reactome Database ID Release 78 9856725 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856725 Reactome R-MMU-190053 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190053.1 1 BRAF dimer complex Reactome DB_ID: 9856739 B-Raf complex Reactome DB_ID: 9856737 Zn2+ Zn++ zinc(2+) Zinc ion Zn(II) Reactome DB_ID: 29426 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 78 29426 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29426 Reactome R-ALL-29426 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29426.3 COMPOUND C00038 2 P28028 phospho-Braf p-S445,S729-BRAF Reactome DB_ID: 9827990 UniProt:P28028 Braf UniProt P28028 445 EQUAL 729 EQUAL 2 EQUAL 766 EQUAL Reactome Database ID Release 78 9827990 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827990 Reactome R-MMU-5672673 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672673.1 1 Ywhab 14-3-3 beta/alpha 14-3-3 protein beta/alpha 1433B_MOUSE Ywhab Reactome DB_ID: 1445100 UniProt:Q9CQV8 Ywhab Ywhab FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2. Negative regulator of signaling cascades that mediate activation of MAP kinases via AKAP13.SUBUNIT Homodimer (By similarity). Interacts with SAMSN1 and PRKCE (PubMed:18604201, PubMed:20478393). Interacts with AKAP13. Interacts with SSH1 and TORC2/CRTC2. Interacts with ABL1; the interaction results in cytoplasmic location of ABL1 and inhibition of cABL-mediated apoptosis. Interacts with ROR2 (dimer); the interaction results in phosphorylation of YWHAB on tyrosine residues. Interacts with GAB2. Interacts with YAP1 (phosphorylated form). Interacts with the phosphorylated (by AKT1) form of SRPK2. Interacts with PKA-phosphorylated AANAT. Interacts with MYO1C. Interacts with SIRT2 (By similarity). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B. Interacts with the 'Ser-1134' and 'Ser-1161' phosphorylated form of SOS1 (By similarity). Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a protein kinase AKT1-dependent manner (By similarity). Interacts with SLITRK1 (By similarity). Interacts with SYNPO2 (phosphorylated form); YWHAB competes with ACTN2 for interaction with SYNPO2 (PubMed:15883195). Interacts with RIPOR2 (via phosphorylated form); this interaction occurs in a chemokine-dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2-mediated RHOA activity (By similarity). Interacts with MARK2 and MARK3 (By similarity). Interacts with TESK1; the interaction is dependent on the phosphorylation of TESK1 'Ser-439' and inhibits TESK1 kinase activity (By similarity). Interacts with MEFV (By similarity).PTM Isoform alpha differs from isoform beta in being phosphorylated (By similarity). Phosphorylated on Ser-60 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.PTM Isoform Short contains a N-acetylmethionine at position 1.SIMILARITY Belongs to the 14-3-3 family. UniProt Q9CQV8 1 EQUAL 246 EQUAL Reactome Database ID Release 78 1445100 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445100 Reactome R-MMU-1445100 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1445100.1 1 Reactome Database ID Release 78 9856737 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856737 Reactome R-MMU-190075 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190075.1 2 Reactome Database ID Release 78 9856739 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856739 Reactome R-MMU-9610125 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610125.1 1 1 Reactome Database ID Release 78 9856751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856751 Reactome R-MMU-190082 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190082.1 2 RAP1:GTP:activated BRAF dimer Reactome DB_ID: 9856729 p-S445,T599,T602,S729 B-Raf complex Reactome DB_ID: 9856723 P28028 phospho-Braf p-S445,T599,S602,S729 BRAF Reactome DB_ID: 9828008 599 EQUAL 602 EQUAL 2 EQUAL 766 EQUAL Reactome Database ID Release 78 9828008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828008 Reactome R-MMU-5672676 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672676.1 1 2 1 Reactome Database ID Release 78 9856723 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856723 Reactome R-MMU-9610128 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610128.1 2 RAP1:GTP Reactome DB_ID: 9856727 1 1 Reactome Database ID Release 78 9856727 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856727 Reactome R-MMU-190069 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-190069.1 1 Reactome Database ID Release 78 9856729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856729 Reactome R-MMU-9610130 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610130.1 2 ACTIVATION activeUnit: #Complex21 Reactome Database ID Release 78 9856752 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856752 Reactome Database ID Release 78 9856754 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856754 Reactome R-MMU-9610163 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610163.1 After recruitment by RAP1 to the endosome, BRAF is activated, likely by autophosphorylation on the activation loop serines at 599 and 602 (Kao et al, 2001; reviewed in Matallanas, 2011). 11278445 Pubmed 2001 Identification of the mechanisms regulating the differential activation of the mapk cascade by epidermal growth factor and nerve growth factor in PC12 cells Kao , S Jaiswal, RK Kolch, W Landreth, GE J Biol Chem 276:18169-77 21779496 Pubmed 2011 Raf family kinases: old dogs have learned new tricks Matallanas, David Birtwistle, Marc Romano, David Zebisch, Armin Rauch, Jens von Kriegsheim, Alexander Kolch, Walter Genes Cancer 2:232-60 LEFT-TO-RIGHT Activated BRAF recruits MAP2Ks and MAPKs to the endosome This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome MAP2K homo/heterodimers Reactome DB_ID: 9828275 MAP2K1 dimer Reactome DB_ID: 9828267 Mek1 Dual specificity mitogen-activated protein kinase kinase 1 Map2k1 MP2K1_MOUSE Reactome DB_ID: 451658 UniProt:P31938 Map2k1 Map2k1 Mek1 Prkmk1 FUNCTION Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (By similarity). Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.ACTIVITY REGULATION Ras proteins such as HRAS mediate the activation of RAF proteins such as RAF1 or BRAF which in turn activate extracellular signal-regulated kinases (ERK) through MAPK (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2. Activation occurs through phosphorylation of Ser-218 and Ser-222 (By similarity). MAP2K1/MEK1 binds KSR1 or KSR2 releasing the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains (By similarity). This allows KSR1 or KSR2 dimerization with BRAF leading to BRAF activation and phosphorylation of MAP2K1 (By similarity). MAP2K1/MEK1 is also the target of negative feed-back regulation by its substrate kinases, such as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating dephosphorylation of the activating residues Ser-218 and Ser-222. Inhibited by serine/threonine phosphatase 2A (By similarity).SUBUNIT Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14 (By similarity). Forms a heterodimer with MAP2K2/MEK2 (PubMed:19219045). Forms heterodimers with KSR2 which further dimerize to form tetramers (By similarity). Interacts with KSR1 or KSR2 and BRAF; the interaction with KSR1 or KSR2 mediates KSR1-BRAF or KSR2-BRAF dimerization (By similarity). Interacts with ARBB2, LAMTOR3, MAPK1/ERK2 and RAF1 (By similarity). Interacts with MORG1 (PubMed:15118098). Interacts with PPARG (By similarity). Interacts with SGK1 (By similarity). Interacts with BIRC6/bruce (By similarity). Interacts with KAT7; the interaction promotes KAT7 phosphorylation (PubMed:23319590). Interacts with RAF1 and NEK10; the interaction is required for ERK1/2-signaling pathway activation in response to UV irradiation (By similarity). Interacts with TRAF3IP3 (By similarity).DOMAIN The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1.PTM Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (BRAF or MEKK1) positively regulates kinase activity (PubMed:8385802). Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK (PubMed:19219045). MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK (PubMed:19219045). Autophosphorylated at Ser-218 and Ser-222, autophosphosphorylation is promoted by NEK10 following UV irradiation (By similarity).DISRUPTION PHENOTYPE Affects fibroblast shape and impairs haptotaxis and adhesion-dependent ERK-signaling.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. UniProt P31938 2 EQUAL 393 EQUAL Reactome Database ID Release 78 451658 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451658 Reactome R-MMU-451658 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-451658.1 2 Reactome Database ID Release 78 9828267 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828267 Reactome R-MMU-5672683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672683.1 MAP2K1:MAPK2K2 heterodimer Reactome DB_ID: 9828271 Map2k2 MAP2K2 Q63932 Reactome DB_ID: 9828269 UniProt:Q63932 Map2k2 UniProt Q63932 1 EQUAL 400 EQUAL Reactome Database ID Release 78 9828269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828269 Reactome R-MMU-59504 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-59504.1 1 1 Reactome Database ID Release 78 9828271 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828271 Reactome R-MMU-5672686 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672686.1 MAP2K2 dimer Reactome DB_ID: 9828273 2 Reactome Database ID Release 78 9828273 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828273 Reactome R-MMU-5672685 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672685.1 Reactome Database ID Release 78 9828275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828275 Reactome R-MMU-5672716 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672716.1 Converted from EntitySet in Reactome MAPKs MAPK1,MAPK3 Reactome DB_ID: 9781105 Mapk1 MAPK1 P63085 Reactome DB_ID: 9758250 UniProt:P63085 Mapk1 Mapk1 Erk2 Mapk Prkm1 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in response to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation. Phosphorylates CDK2AP2 (By similarity).FUNCTION Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity.ACTIVITY REGULATION Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-183 and Tyr-185 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Phosphorylation on Ser-27 by SGK1 results in its activation by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Dephosphorylated and inactivated by DUSP1, DUSP3, DUSP6 and DUSP9. Inactivated by pyrimidylpyrrole inhibitors.SUBUNIT Binds both upstream activators and downstream substrates in multimolecular complexes. This interaction inhibits its tyrosine-kinase activity. Interacts with ADAM15, ARHGEF2, ARRB2, DAPK1 (via death domain), HSF4, IER3, IPO7, DUSP6, NISCH, SGK1, and isoform 1 of NEK2. Interacts (via phosphorylated form) with TPR (via C-terminal region and phosphorylated form); the interaction requires dimerization of MAPK1/ERK2 and increases following EGF stimulation (By similarity). Interacts (phosphorylated form) with CAV2 ('Tyr-19'-phosphorylated form); the interaction, promoted by insulin, leads to nuclear location and MAPK1 activation. Interacts with DCC (By similarity). Interacts with MORG1 (PubMed:15118098). Interacts with PEA15 (PubMed:16162500). Interacts with MKNK2. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation (PubMed:11702783). The phosphorylated form interacts with PML. Interacts with STYX. Interacts with CDK2AP2. Interacts with CAVIN4 (By similarity). Interacts with DUSP7; the interaction enhances DUSP7 phosphatase activity (PubMed:27783954). Interacts with GIT1; this interaction is necessary for MAPK1 localization to focal adhesions (PubMed:15923189). Interacts with ZNF263 (By similarity).TISSUE SPECIFICITY Widely expressed.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-183 and Tyr-185, which activates the enzyme. Ligand-activated ALK induces tyrosine phosphorylation (By similarity). Dephosphorylated by PTPRJ at Tyr-185 (By similarity). Phosphorylated upon FLT3 and KIT signaling (By similarity). Dephosphorylated by DUSP1 at Thr-183 and Tyr-185 (PubMed:8221888).PTM ISGylated.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt P63085 2 EQUAL 360 EQUAL Reactome Database ID Release 78 9758250 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9758250 Reactome R-MMU-59282 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-59282.1 Mapk3 MAPK3 Q63844 Reactome DB_ID: 9758247 UniProt:Q63844 Mapk3 Mapk3 Erk1 Prkm3 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.ACTIVITY REGULATION Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-203 and Tyr-205 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Dephosphorylated and inactivated by DUSP3, DUSP6 and DUSP9.SUBUNIT Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS, MAP2K1/MEK1, MAPK3 and RGS14. Interacts with TPR. Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, NISCH, and SGK1 (By similarity). Interacts with MORG1 (PubMed:15118098). Interacts with PEA15 (PubMed:11702783). Interacts with isoform 1 of MKNK2 and this binding prevents from dephosphorylation and inactivation (PubMed:16162500). Interacts with CDKN2AIP. Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs upon heat shock. Interacts with CAVIN4 (By similarity). Interacts with GIT1; this interaction is necessary for MAPK3 localization to focal adhesions (PubMed:15923189). Interacts with ZNF263 (By similarity).DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-203 and Tyr-205, which activates the enzyme. Ligand-activated ALK induces tyrosine phosphorylation (By similarity). Dephosphorylated by PTPRJ at Tyr-205 (By similarity). Autophosphorylated on threonine and tyrosine residues in vitro. Phosphorylated upon FLT3 and KIT signaling (By similarity).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt Q63844 2 EQUAL 379 EQUAL Reactome Database ID Release 78 9758247 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9758247 Reactome R-MMU-59284 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-59284.1 Reactome Database ID Release 78 9781105 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781105 Reactome R-MMU-169291 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169291.1 RAP1:GTP:activated BRAF dimer:MAPK2K:MAPK complex Reactome DB_ID: 9856731 1 1 1 Reactome Database ID Release 78 9856731 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856731 Reactome R-MMU-9610134 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610134.1 Reactome Database ID Release 78 9856733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856733 Reactome R-MMU-9610152 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610152.1 Downstream of NGF stimulation and RAP1 activation, BRAF recruits MAP2Ks and MAPKs to the endosome to promote sustained RAF/MAPK signaling (York et al, 1998; reviewed in Reichardt, 2006; Barford et al, 2017). 27503831 Pubmed 2017 The neurotrophin receptor signaling endosome: Where trafficking meets signaling Barford, Kelly Deppmann, Christopher Winckler, Bettina Dev Neurobiol 77:405-418 LEFT-TO-RIGHT 2.7.11 Activated BRAF phosphorylates MAP2K dimers downstream of RAP1 and NGF This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 4 RAP1:GTP:activated BRAF dimer:p-2S MAPK2K:MAPK complex Reactome DB_ID: 9856735 Converted from EntitySet in Reactome p-2S MAP2K homo/heterodimers Reactome DB_ID: 9828240 p-2S MAP2K1:p-2S MAPK2K2 heterodimer Reactome DB_ID: 9828234 Map2k1 Phospho Mek1 Dual specificity mitogen-activated protein kinase kinase 1 MP2K1_MOUSE Reactome DB_ID: 451693 218 EQUAL 222 EQUAL 2 EQUAL 393 EQUAL Reactome Database ID Release 78 451693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451693 Reactome R-MMU-451693 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-451693.1 1 Q63932 phospho-Map2k2 p-S222,S226-MAP2K2 Reactome DB_ID: 9828232 222 EQUAL 226 EQUAL 1 EQUAL 400 EQUAL Reactome Database ID Release 78 9828232 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828232 Reactome R-MMU-169292 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169292.1 1 Reactome Database ID Release 78 9828234 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828234 Reactome R-MMU-5672705 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672705.1 p-S218,S222 MAP2K1 dimer Reactome DB_ID: 9828236 2 Reactome Database ID Release 78 9828236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828236 Reactome R-MMU-5672703 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672703.1 p-S222,S226 MAP2K2 dimer Reactome DB_ID: 9828238 2 Reactome Database ID Release 78 9828238 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828238 Reactome R-MMU-5672701 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672701.1 Reactome Database ID Release 78 9828240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828240 Reactome R-MMU-5672721 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5672721.1 1 1 1 Reactome Database ID Release 78 9856735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856735 Reactome R-MMU-9610136 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610136.1 4 ACTIVATION activeUnit: #Complex21 Reactome Database ID Release 78 9856740 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856740 Reactome Database ID Release 78 9856742 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856742 Reactome R-MMU-9610153 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610153.1 Downstream of NGF stimulation, activated BRAF phosphorylates MAP2K1 and MAP2K2 (MEK1 and MEK2) at the endosome, leading to sustained MAPK signaling (York et al, 1998; Kao et al, 2001; reviewed in Huang and Reichardt, 2003; Reichardt, 2006). 12676795 Pubmed 2003 Trk receptors: roles in neuronal signal transduction Huang, EJ Reichardt, LF Annu Rev Biochem 72:609-42 LEFT-TO-RIGHT 2.7.11 MAP2Ks phosphorylate MAPKs downstream of BRAF and NGF This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 4 RAP1:GTP:activated BRAF dimer:p-2S MAPK2K:p-T,Y MAPK complex Reactome DB_ID: 9856744 1 1 Converted from EntitySet in Reactome p-T,Y MAPKs Reactome DB_ID: 9781111 Q63844 phospho-Mapk3 p-T202,Y204-MAPK3 Reactome DB_ID: 9758324 202 EQUAL 204 EQUAL 2 EQUAL 379 EQUAL Reactome Database ID Release 78 9758324 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9758324 Reactome R-MMU-109842 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109842.1 P63085 phospho-Mapk1 p-T185,Y187-MAPK1 Reactome DB_ID: 9758340 185 EQUAL 187 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 78 9758340 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9758340 Reactome R-MMU-109853 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109853.1 Reactome Database ID Release 78 9781111 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781111 Reactome R-MMU-169289 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169289.1 1 Reactome Database ID Release 78 9856744 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856744 Reactome R-MMU-9610140 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610140.1 4 ACTIVATION activeUnit: #Complex26 Reactome Database ID Release 78 9856747 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856747 Reactome Database ID Release 78 9856749 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856749 Reactome R-MMU-9610156 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610156.1 Activated MAP2K1 and MAP2K2 dimers phosphorylate MAPK1 and MAPK3 downstream of NGF stimulation and RAP1 activation at the endosome (Kao et al, 2001; Wu et al, 2001; reviewed in Huang and Reichardt, 2003; Reichardt, 2006). LEFT-TO-RIGHT Dissociation of phosphorylated MAP2Ks and MAPKs This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome Database ID Release 78 9856746 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856746 Reactome R-MMU-9610154 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610154.1 The mechanisms governing dissocation of activated signaling complexes downstream of NGF and RAP1 stimulation are not fully worked out, however phosphorylated MAPK dimers are known to phosphorylate cytosolic and nuclear targets that promote neuronal gene expression and differentiation (Nguyen et al, 1993; reviewed in Vaudry et al, 2002; Santiago and Bashaw, 2014). 8387505 Pubmed 1993 Co-regulation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1, and the 90-kDa ribosomal S6 kinase in PC12 cells. Distinct effects of the neurotrophic factor, nerve growth factor, and the mitogenic factor, epidermal growth factor Nguyen, Tien T Scimeca, Jean Claude Filloux, Chantal Peraldi, Pascal Carpentier, Jean Loius Van Obberghen, Emmanuel J. Biol. Chem. 268:9803-10 12040181 Pubmed 2002 Signaling pathways for PC12 cell differentiation: making the right connections Vaudry, D Stork, P J S Lazarovici, P Eiden, L E Science 296:1648-9 25468936 Pubmed 2014 Transcription factors and effectors that regulate neuronal morphology Santiago, Celine Bashaw, Greg J Development 141:4667-80 LEFT-TO-RIGHT p-T,Y MAPKs dimerize This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 Converted from EntitySet in Reactome p-ERK dimer p-T,Y MAPK dimers Reactome DB_ID: 9764810 p-T202, Y204 MAPK3 dimer Reactome DB_ID: 9764806 2 Reactome Database ID Release 78 9764806 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764806 Reactome R-MMU-109844 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109844.1 p-T185,Y187 MAPK1 dimer Reactome DB_ID: 9764808 2 Reactome Database ID Release 78 9764808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764808 Reactome R-MMU-109855 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109855.1 Reactome Database ID Release 78 9764810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764810 Reactome R-MMU-1268261 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1268261.1 Reactome Database ID Release 78 9828377 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828377 Reactome R-MMU-5674385 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5674385.1 Phosphorylated MAPK monomers can dimerize - generally into MAPK1 and MAPK3 homodimers, as the heterodimer is unstable- but the physiological significance of dimerization is unclear (Khokhlatchev et al, 1998; reviewed Rosokoski, 2012b). MAPKs have both cytosolic and nuclear targets and dimerization may be particularly important for MAPK-dependent phosphorylation of cytosolic targets. Phosphorylation of cytosolic MAPK targets appears to happen predominantly in the context of larger scaffolding complexes, and since the scaffolds and cytosolic MAPK substrates contact the same hydrophobic surface of MAPK, dimerization is necessary to allow assembly of a functional complex (Casar et al, 2008; Lidke et al, 2010; reviewed in Casar et al, 2009). Consistent with this, disrupting either MAPK dimerization or the MAPK interaction with the scaffolding protein abrogated proliferation and transformation (Casar et al, 2008). Note that, for simplicity in this diagram, dimerization is shown as happening between free cytosolic monomers of activated MAPK rather than in the context of the scaffolding complex.<br>Although predominantly cytoplasmic in resting cells, a proportion of activated MAPK translocates to the nucleus upon stimulation where it activates nuclear targets. Despite early studies to the suggesting that dimerization was required for nuclear translocation, a few recent papers have challenged this notion (Lenormand et al, 1993; Chen et al, 1992; Khokhlatchev et al, 1998; Casar et al, 2008; Lidke et al, 2010; Burack and Shaw, 2005; reviewed in Roskoski, 2012b). 1545823 Pubmed 1992 Nuclear localization and regulation of erk- and rsk-encoded protein kinases Chen, Rey-Huei Sarnecki, Charlyn Blenis, John Mol. Cell. Biol. 12:915-27 15546878 Pubmed 2005 Live Cell Imaging of ERK and MEK: simple binding equilibrium explains the regulated nucleocytoplasmic distribution of ERK Burack, W Richard Shaw, Andrey S J. Biol. Chem. 280:3832-7 9604935 Pubmed 1998 Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation Khokhlatchev, AV Canagarajah, B Wilsbacher, J Robinson, M Atkinson, M Goldsmith, E Cobb, MH Cell 93:605-15 19920141 Pubmed 2010 ERK nuclear translocation is dimerization-independent but controlled by the rate of phosphorylation Lidke, Diane S Huang, Fang Post, Janine N Rieger, Bernd Wilsbacher, Julie Thomas, JL Pouysségur, Jacques Jovin, Thomas M Lenormand, Philippe J. Biol. Chem. 285:3092-102 8394845 Pubmed 1993 Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts Lenormand, Phillipe Sardet, Claude Pagès, Gilles L'Allemain, Gilles Brunet, Anne Pouysségur, Jacques J. Cell Biol. 122:1079-88 22569528 Pubmed 2012 ERK1/2 MAP kinases: structure, function, and regulation Roskoski, Robert Jr Pharmacol. Res. 66:105-43 19279408 Pubmed 2009 ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task Casar, Berta Pinto, Adán Crespo, Piero Cell Cycle 8:1007-13 18775330 Pubmed 2008 Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes Casar, Berta Pinto, Adán Crespo, Piero Mol. Cell 31:708-21 LEFT-TO-RIGHT p-T,Y MAPK dimers translocate to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome p-T,Y MAPK dimers Phospho-ERK dimer Reactome DB_ID: 9769091 p-T202, Y204 MAPK3 dimer Reactome DB_ID: 9755353 nucleoplasm GENE ONTOLOGY GO:0005654 Q63844 phospho-Mapk3 p-T202,Y204-MAPK3 Reactome DB_ID: 9755351 2 EQUAL 379 EQUAL Reactome Database ID Release 78 9755351 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9755351 Reactome R-MMU-112359 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-112359.1 2 Reactome Database ID Release 78 9755353 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9755353 Reactome R-MMU-109845 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109845.1 p-Y185,Y187 MAPK1 dimer Reactome DB_ID: 9769089 P63085 phospho-Mapk1 p-T185,Y187-MAPK1 Reactome DB_ID: 9763898 2 EQUAL 360 EQUAL Reactome Database ID Release 78 9763898 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9763898 Reactome R-MMU-112354 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-112354.1 2 Reactome Database ID Release 78 9769089 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769089 Reactome R-MMU-109856 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109856.1 Reactome Database ID Release 78 9769091 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769091 Reactome R-MMU-198701 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198701.1 Reactome Database ID Release 78 9856756 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856756 Reactome R-MMU-9610166 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610166.1 After phosphorylation by MAP2Ks, a proportion of activated MAPK dimers translocate into the nucleus where it activates nuclear targets involved in neuronal differentiation (Mullenbrock et al, 2011; Adams et al, 2017; reviewed in Santiago and Bashaw, 2014). Although dimerization of MAPKs was originally thought to be critcal for nuclear translocation, a number of studies have now challenged the physiological relevance of MAPK dimerization, and this remains an area of uncertainty (reviewed in Casar et al, 2009; Roskoski, 2012). 22065583 Pubmed 2011 Global expression analysis identified a preferentially nerve growth factor-induced transcriptional program regulated by sustained mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) and AP-1 protein activation during PC12 cell differentiation Mullenbrock, Steven Shah, Janki Cooper, Geoffrey M J. Biol. Chem. 286:45131-45 28076410 Pubmed 2017 Role for Egr1 in the Transcriptional Program Associated with Neuronal Differentiation of PC12 Cells Adams, Kenneth W Kletsov, Sergey Lamm, Ryan J Elman, Jessica S Mullenbrock, Steven Cooper, Geoffrey M PLoS ONE 12:e0170076 Reactome Database ID Release 78 9860920 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860920 Reactome R-MMU-170968 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-170968.1 GENE ONTOLOGY GO:0000165 The adaptor protein Frs2 (Fibroblast growth factor receptor substrate 2) can mediate the prolonged activation of the MAPK (ERK) cascade. 9069267 Pubmed 1997 Signal transduction by the neurotrophin receptors Kaplan, DR Miller, FD Curr Opin Cell Biol 9:213-21 ARMS-mediated activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.10.1 ARMS is phosphorylated by active TrkA receptor This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Active TrkA receptor:ARMS:Crk complex Reactome DB_ID: 9764328 ARMS:Crk Reactome DB_ID: 9764326 Crk CRK Q64010 Reactome DB_ID: 9764305 UniProt:Q64010 Crk UniProt Q64010 1 EQUAL 304 EQUAL Reactome Database ID Release 78 9764305 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764305 Reactome R-MMU-2980677 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2980677.1 1 E9Q9B7 Kidins220 KIDINS220 Reactome DB_ID: 9764324 UniProt:E9Q9B7 Kidins220 UniProt E9Q9B7 1 EQUAL 1771 EQUAL Reactome Database ID Release 78 9764324 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764324 Reactome R-MMU-169880 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169880.1 1 Reactome Database ID Release 78 9764326 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764326 Reactome R-MMU-169872 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169872.1 1 1 Reactome Database ID Release 78 9764328 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764328 Reactome R-MMU-169871 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169871.1 Active TrkA receptor:Phospho-ARMS:Crk complex Reactome DB_ID: 9764309 1 Phospho-ARMS:Crk Reactome DB_ID: 9764307 1 E9Q9B7 phospho-Kidins220 p-Y1096-KIDINS220 Reactome DB_ID: 9764301 1096 EQUAL 1 EQUAL 1771 EQUAL Reactome Database ID Release 78 9764301 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764301 Reactome R-MMU-169869 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169869.1 1 Reactome Database ID Release 78 9764307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764307 Reactome R-MMU-169854 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169854.1 1 Reactome Database ID Release 78 9764309 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764309 Reactome R-MMU-169865 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169865.1 ACTIVATION GENE ONTOLOGY GO:0004714 Reactome Database ID Release 78 9764329 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764329 Reactome Database ID Release 78 9764331 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764331 Reactome R-MMU-169905 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169905.1 Phosphorylation of ARMS by Trk receptor (on tyrosine 1096) enables ARMS to recruit Crk via it's SH2 domain and freeing the SH3 domain. The SH3 domain of Crk is then free to bind C3G for MAP kinase activation. 16284401 Pubmed 2006 Identification of a switch in neurotrophin signaling by selective tyrosine phosphorylation Arevalo, JC Pereira, DB Yano, H Teng, KK Chao, MV J Biol Chem 281:1001-7 LEFT-TO-RIGHT Crk's SH3 domain engages C3G This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome Database ID Release 78 9764311 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764311 Reactome R-MMU-169895 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169895.1 Rap guanine nucleotide exchange factor 1 (RAPGEF1, C3G) is a guanine nucleotide exchange factor for Rap1, which is recruited by Crk adaptor proteins (Knudsen et al. 1994; York, 1998). LEFT-TO-RIGHT C3G stimulates nucleotide exchange on Rap1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Rap1-GDP Reactome DB_ID: 9764317 GDP Guanosine 5'-diphosphate Guanosine diphosphate GDP(3-) Reactome DB_ID: 29420 GDP(3-) [ChEBI:58189] GDP(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate(3-) GDP guanosine 5'-diphosphate trianion guanosine 5'-diphosphate GDP trianion ChEBI CHEBI:58189 Reactome Database ID Release 78 29420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29420 Reactome R-ALL-29420 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29420.3 COMPOUND C00035 1 Rap1a RAP1A P62835 Reactome DB_ID: 9764315 1 EQUAL 181 EQUAL Reactome Database ID Release 78 9764315 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764315 Reactome R-MMU-169884 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169884.1 1 Reactome Database ID Release 78 9764317 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764317 Reactome R-MMU-169860 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169860.1 Rap1-GTP Reactome DB_ID: 9764319 1 1 Reactome Database ID Release 78 9764319 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764319 Reactome R-MMU-169866 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169866.1 ACTIVATION GENE ONTOLOGY GO:0005085 Reactome Database ID Release 78 9764320 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764320 Reactome Database ID Release 78 9764322 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764322 Reactome R-MMU-169904 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169904.1 Rap1 is a small G protein, necessary for prolonged ERK activity in PC12 cells. In such cells, NGF triggers a program of neuronal differentiation through the activation of a Rap1:B-RAF:ERK module Rap1 is activated by NGF, but not by epidermal growth factor (EGF), although both growth factors cause transient activation of RAS. Activation of Rap1 by NGF requires internalization of TRKA to intracellular vesicles, mostly endosomes, containing Rap1, B-RAF, MEK and ERKs. Rap1 does not co-localize with RAS. Therefore, the ability of Rap1 to bind RAF-1 without activating it might sequester RAF-1 from RAS. Activation of GEFs that couple to Rap1 as well as RAS might provide a mechanism to limit signals to RAS. Reactome Database ID Release 78 9860882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860882 Reactome R-MMU-170984 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-170984.1 ARMS (Ankyrin-Rich Membrane Spanning/Kidins 220) is a 220kD tetraspanning adaptor protein which becomes rapidly tyrosine phosphorylated by active Trk receptors. ARMS is another adaptor protein which is involved in the activation of Rap1 and the subsequent prolonged activation of the MAPK cascade. Reactome Database ID Release 78 9860884 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860884 Reactome R-MMU-169893 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-169893.1 After NGF binding, activated Trk receptors provide multiple docking sites for adaptor proteins and enzymes. Two docking proteins, the Ankyrin-Rich Membrane Spanning protein (ARMS/Kidins220) and Fibroblast growth factor receptor substrate 2 (Frs2), target signaling molecules in response to NGF stimulation and link receptor activation with the MAP kinase (also called the Extracellular signal-Regulated Kinase cascade, ERK) cascade, an essential process for growth factor-induced cell proliferation and differentiation.<br>A feature of NGF signaling is the sustained activation of the MAPK cascade. This is achieved by the small G protein, Rap1 which binds to and activates B-Raf, an activator of the MAPK cascade. Rap1 is a member of the Ras family of G proteins and like all G proteins, Rap1 is in an inactive state when bound to GDP and is active when bound to GTP. A specific GEF (guanine nucleotide exchange factor) called C3G can activate Rap1 by exchanging GDP for GTP. 12765839 Pubmed 2003 Does Rap1 deserve a bad Rap? Stork, PJ Trends Biochem Sci 28:267-75 Reactome Database ID Release 78 9860886 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860886 Reactome R-MMU-187687 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187687.1 Neurotrophins utilize multiple pathways to activate ERKs (ERK1 and ERK2), a subgroup of the large MAP kinase (MAPK) family, from the plasma membrane. The major signalling pathways to ERKs are via RAS, ocurring from caveolae in the plasma membrane or from clathrin-coated vesicles, and via RAP1, taking place in early endosomes. Whereas RAS activation by NGF is transient, RAP1 activation by NGF is sustained for hours. 10508738 Pubmed 1999 Extracellular-signal-regulated kinase signalling in neurons Grewal, SS York, Randall D Stork, PJ Curr Opin Neurobiol 9:544-53 PI3K/AKT activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Active IRS recruits PI3K to the plasma membrane and activates it This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PI3K Reactome DB_ID: 9756248 Converted from EntitySet in Reactome PI3K-catalytic subunit Reactome DB_ID: 9756246 Pik3ca Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform PK3CA_MOUSE Reactome DB_ID: 9027214 UniProt:P42337 Pik3ca Pik3ca FUNCTION Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides. Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Also has serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS. Plays a role in the positive regulation of phagocytosis and pinocytosis (PubMed:19604150).PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3) (PubMed:8139567). Interacts with IRS1 in nuclear extracts (PubMed:15197263). Interacts with RUFY3. Interacts with RASD2. Interacts with APPL1 (By similarity). Interacts with HRAS and KRAS (PubMed:17540175). Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2 (PubMed:17540175). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (By similarity).DOMAIN The PI3K-ABD domain and the PI3K-RBD domain interact with the PI3K/PI4K kinase domain. The C2 PI3K-type domain may facilitate the recruitment to the plasma membrane. The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1, and the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1.DISRUPTION PHENOTYPE Lethal. Embryonic fibroblasts cells are resistant to oncogenic transformation induced by oncogenic receptor tyrosine kinases (RTKs), are unable to differentiate into adipocytes and deficient in cellular signaling in response to various growth factors. Defective responsiveness to insulin led to reduced somatic growth, hyperinsulinemia, glucose intolerance, hyperphagia and increased adiposity.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt P42337 1 EQUAL 1068 EQUAL Reactome Database ID Release 78 9027214 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9027214 Reactome R-MMU-9027214 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9027214.1 Pik3cb PIK3CB Q8BTI9 Reactome DB_ID: 9756244 UniProt:Q8BTI9 Pik3cb Pik3cb FUNCTION Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) derivatives at position 3 of the inositol ring to produce 3-phosphoinositides. Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (By similarity). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors.PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CB and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interaction with PIK3R2 is required for nuclear localization and nuclear export (By similarity). Part of a complex with PIK3R1 and PTEN (By similarity). Binding to PTEN may antagonize the lipid kinase activity under normal growth conditions (By similarity). Part of a complex involved in autophagosome formation composed of PIK3C3 and PIK3R4. Interacts with BECN1, ATG14 and RAB5A.DOMAIN The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1; the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1; and the PI3K/PI4K kinase domain with the cSH2 (C-terminal SH2) region of PIK3R1. The inhibitory interaction between the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1 is weak. The nuclear localization signal (NLS) is required for its function in cell survival (By similarity).PTM Phosphorylation at Ser-1064 down-regulates lipid kinase activity.DISRUPTION PHENOTYPE Mice have defects in autophagosome formation. Have normal bleeding time but are resistant to thrombosis after arterial injury. Mice fail to induce tumors in a model of prostate tumor formation induced by Pten loss.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt Q8BTI9 1 EQUAL 1070 EQUAL Reactome Database ID Release 78 9756244 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756244 Reactome R-MMU-74788 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-74788.1 Reactome Database ID Release 78 9756246 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756246 Reactome R-MMU-74689 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-74689.1 1 Converted from EntitySet in Reactome PI3K-regulatory subunit Reactome DB_ID: 9756240 Pik3r1 PIK3R1 P26450 Reactome DB_ID: 9756235 UniProt:P26450 Pik3r1 Pik3r1 FUNCTION Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling (By similarity). Modulates the cellular response to ER stress by promoting nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (PubMed:20348926).SUBUNIT Heterodimer of a regulatory subunit PIK3R1 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts (via SH2 domains) with CCDC88A/GIV (tyrosine-phosphorylated form); the interaction enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration (By similarity). Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (PubMed:20348926). Interacts with PIK3R2; the interaction is dissociated in an insulin-dependent manner (PubMed:20348926). Interacts with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with IRS1 and phosphorylated IRS4. Interacts with NISCH and RUFY3 (By similarity). Interacts with phosphorylated TOM1L1. Interacts with phosphorylated LIME1 upon TCR or BCR activation. Interacts with CBLB. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with SOCS7 and HCST. Interacts with AXL, FASLG, FGR, HCK, KIT and BCR. Interacts with PTK2/FAK1 (By similarity). Interacts with PDGFRB (tyrosine phosphorylated) (By similarity). Interacts with NTRK1 (phosphorylated upon ligand-binding) (By similarity). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:9312046). Interacts with FER. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated) (Probable). Interacts with PDGFRA (tyrosine phosphorylated). Interacts with LYN (via SH3 domain); this enhances enzyme activity. Interacts with ERBB4. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (By similarity). Interacts with APPL1 and APPL2 (PubMed:25328665). Interacts with SRC (By similarity). Interacts with ALOX5; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS) (By similarity).DOMAIN The SH3 domain mediates the binding to CBLB.PTM Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation.PTM Phosphorylated. Tyrosine phosphorylated in response to signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Dephosphorylated by PTPRJ. Phosphorylated by PIK3CA at Ser-608; phosphorylation is stimulated by insulin and PDGF. The relevance of phosphorylation by PIK3CA is however unclear. Phosphorylated in response to KIT and KITLG/SCF. Phosphorylated by FGR (By similarity). Phosphorylated by CSF1R. Phosphorylated by ERBB4. Phosphorylated on tyrosine residues by TEK/TIE2.SIMILARITY Belongs to the PI3K p85 subunit family. UniProt P26450 1 EQUAL 724 EQUAL Reactome Database ID Release 78 9756235 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756235 Reactome R-MMU-74789 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-74789.1 Pik3r2 PIK3R2 O08908 Reactome DB_ID: 9756238 UniProt:O08908 Pik3r2 Pik3r2 FUNCTION Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Binds to activated (phosphorylated) protein-tyrosine kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Indirectly regulates autophagy (By similarity). Promotes nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (PubMed:20348926).SUBUNIT Heterodimer of a regulatory subunit PIK3R2 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts with AXL. Interacts with FLT1 (tyrosine-phosphorylated) and FLT4 (tyrosine-phosphorylated) (By similarity). Interacts with FBXL2; PIK3R2 is a substrate of the SCF(FBXL2) complex. Interacts with PTPN13; dephosphorylates PIK3R2 (By similarity). Interacts with NYAP1, NYAP2 and MYO16 (PubMed:21946561). Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (PubMed:20348926). Interacts with PIK3R1; the interaction is dissociated in an insulin-dependent manner (PubMed:20348926). Interacts with SRC (By similarity).DOMAIN The SH2 2 domain is required for interaction with FBXL2 and PTPN13.PTM Phosphorylated in response to signaling from activated receptor-type protein kinases. Dephosphorylated by PTPRJ. Dephosphorylated at Tyr-649 by PTPN13. Phosphorylation of Tyr-649 impairs while its dephosphorylation promotes interaction with FBXL2 and SCF(FBXL2)-mediated polyubiquitination.PTM Ubiquitinated. Polyubiquitination by the SCF(FBXL2) complex probably promotes proteasomal degradation of PIK3R2.SIMILARITY Belongs to the PI3K p85 subunit family. UniProt O08908 1 EQUAL 728 EQUAL Reactome Database ID Release 78 9756238 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756238 Reactome R-MMU-74791 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-74791.1 Reactome Database ID Release 78 9756240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756240 Reactome R-MMU-74688 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-74688.1 1 Reactome Database ID Release 78 9756248 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756248 Reactome R-MMU-74693 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-74693.1 Activated TrkA receptor:Phospho-IRS1/2 Reactome DB_ID: 9768953 2 1 Converted from EntitySet in Reactome p-Y-IRS1,p-Y-IRS2 Reactome DB_ID: 9756049 P35569 phospho-Irs1 p-Y-IRS1 Reactome DB_ID: 9756045 UniProt:P35569 Irs1 Irs1 Irs-1 FUNCTION May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (By similarity).SUBUNIT Interacts (via phosphorylated YXXM motifs) with PIK3R1 (By similarity). Interacts with ROCK1 (By similarity). Interacts with GRB2 (By similarity). Interacts with SOCS7 (By similarity). Interacts (via IRS-type PTB domain) with IGF1R and INSR (via the tyrosine-phosphorylated NPXY motif) (By similarity). Interacts with UBTF and PIK3CA (PubMed:15197263). Interacts (via PH domain) with PHIP (PubMed:11018022). Interacts with FER (PubMed:11006284). Interacts with ALK (By similarity). Interacts with EIF2AK2/PKR (PubMed:22948222). Interacts with GKAP1 (PubMed:25586176). Interacts with DGKZ in the absence of insulin; insulin stimulation decreases this interaction (PubMed:27739494). Found in a ternary complex with DGKZ and PIP5K1A in the absence of insulin stimulation (PubMed:27739494).TISSUE SPECIFICITY Expressed in osteoblasts, but not in osteoclasts.PTM Serine phosphorylation of IRS1 is a mechanism for insulin resistance. Ser-307 phosphorylation inhibits insulin action through disruption of IRS1 interaction with the insulin receptor (By similarity). Phosphorylation of Tyr-891 is required for GRB2-binding (By similarity). Phosphorylated by ALK. Phosphorylated at Ser-265, Ser-302, Ser-632 and Ser-1097 by RPS6KB1; phosphorylation induces accelerated degradation of IRS1 (By similarity). Phosphorylated on tyrosine residues in response to insulin (PubMed:25586176). In skeletal muscles, dephosphorylated on Tyr-608 by TNS2 under anabolic conditions; dephosphorylation results in the proteasomal degradation of IRS1 (By similarity).PTM Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-dependent manner, leading to its degradation: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2). UniProt P35569 1 EQUAL 1242 EQUAL Reactome Database ID Release 78 9756045 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756045 Reactome R-MMU-74772 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-74772.1 P81122 phospho-Irs2 p-Y-IRS2 Reactome DB_ID: 9756047 UniProt:P81122 Irs2 Irs2 FUNCTION May mediate the control of various cellular processes by insulin.SUBUNIT Interacts with PHIP.TISSUE SPECIFICITY Skeletal muscle, lung, brain, liver, kidney, heart and spleen. UniProt P81122 1 EQUAL 1338 EQUAL Reactome Database ID Release 78 9756047 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756047 Reactome R-MMU-74774 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-74774.1 Reactome Database ID Release 78 9756049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756049 Reactome R-MMU-112322 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-112322.1 1 Reactome Database ID Release 78 9768953 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768953 Reactome R-MMU-198299 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198299.1 Activated TrkA receptor:Phospho-IRS1/2:PI3K(p85:p110) Reactome DB_ID: 9768955 1 1 Reactome Database ID Release 78 9768955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768955 Reactome R-MMU-213135 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-213135.1 Reactome Database ID Release 78 9768957 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768957 Reactome R-MMU-198315 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198315.1 The PI3K regulatory subunit p85 binds to IRS1 or IRS2, tyrosine-phosphorylated at YXXM motifs, through its SH2 domain.<br>As the p85 subunt is constitutively associated with the p110 catalytic subunit, the outcome is that the whole PI3K complex is recruited to the membrane. The interaction at the plasma membrane of the p85 regulatory subunit with the p110 catalytic subunit of PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) causes a conformational change, resulting in activation of the catalytic subunit (Miranda et al. 2001). 11147812 Pubmed 2001 IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1 Miranda, C Greco, A Miele, C Pierotti, MA Van Obberghen, E J Cell Physiol 186:35-46 LEFT-TO-RIGHT 2.7.1.153 PI3K produces PIP3 and other phosphatidyl inositides This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PIP2 PI(4,5)P2 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate Phosphatidylinositol-4,5-bisphosphate 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate Reactome DB_ID: 179856 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate PIP2 ChEBI CHEBI:18348 Reactome Database ID Release 78 179856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179856 Reactome R-ALL-179856 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179856.3 COMPOUND C04637 PIP3 PI(3,4,5)P3 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate Phosphatidylinositol-3,4,5-trisphosphate Reactome DB_ID: 179838 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate PIP3 ChEBI CHEBI:16618 Reactome Database ID Release 78 179838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179838 Reactome R-ALL-179838 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179838.3 COMPOUND C05981 ACTIVATION activeUnit: #Complex49 Phospho-IRS1/2:PI3K(p85:p110) Reactome DB_ID: 9768901 1 Converted from EntitySet in Reactome Phospho-IRS1/2 (by TRKA) Reactome DB_ID: 9768899 P35569 phospho-Irs1 p-Y-IRS1 Reactome DB_ID: 9768895 1 EQUAL 1242 EQUAL Reactome Database ID Release 78 9768895 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768895 Reactome R-MMU-198366 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198366.1 P81122 phospho-Irs2 p-Y-IRS2 Reactome DB_ID: 9768897 1 EQUAL 1338 EQUAL Reactome Database ID Release 78 9768897 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768897 Reactome R-MMU-198334 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198334.1 Reactome Database ID Release 78 9768899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768899 Reactome R-MMU-198369 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198369.1 1 Reactome Database ID Release 78 9768901 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768901 Reactome R-MMU-198344 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198344.1 GENE ONTOLOGY GO:0046934 Reactome Database ID Release 78 9768902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768902 Reactome Database ID Release 78 9768904 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9768904 Reactome R-MMU-198266 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198266.1 PI3-kinase phosphorylates several phosphatidyl-inositides (phospholipids) at the plasma membrane: the most relevant is PtdIns(3,4,5)P3, also named PIP3. 12167717 Pubmed 2002 Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B Scheid, MP Marignani, PA Woodgett, JR Mol Cell Biol 22:6247-60 LEFT-TO-RIGHT PIP3 binds to RhoA and activates it This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Rhoa Transforming protein RhoA Reactome DB_ID: 5625902 UniProt:Q9QUI0 Rhoa Rhoa Arha Arha2 FUNCTION Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state (PubMed:14697203). Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis (By similarity). Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion (PubMed:11777936, PubMed:20974804). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (By similarity). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis. Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center (By similarity). May be an activator of PLCE1 (PubMed:9635436). In neurons, involved in the inhibiton of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (PubMed:14697203).ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. Activated by GEFs such as ARHGEF2, ARHGEF3, ARHGEF28 and BCR. Inhibited by GAPs such as ARHGAP30. Inhibited by GDP dissociation inhibitors such as ARHGDIA.SUBUNIT Interacts with ARHGEF28 (PubMed:11058585). Interacts (via GTP-bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases. Interacts with RIPOR2 (via active GTP- or inactive GDP-bound forms) isoform 1 and isoform 2; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes. Binds PRKCL1, ROCK1 and ROCK2 (By similarity). Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN (PubMed:9535835, PubMed:8662891). Interacts with PLCE1 and AKAP13 (By similarity). Interacts with DIAPH1 (PubMed:9214622). Interacts (in the constitutively activated, GTP-bound form) with DGKQ. Interacts with RACK1; enhances RHOA activation. Interacts with PKP4; the interaction is detected at the midbody (By similarity). Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2 (PubMed:20974804). Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA. Interacts with ARHGDIB (By similarity). Interacts (GTP-bound form) with KCNA2 (via cytoplasmic N-terminal domain) (PubMed:9635436). Interacts (GTP-bound form) with ECT2; the interaction results in allosteric activation of ECT2 (By similarity).INDUCTION Up-regulated during keratinocyte differentiation.PTM Ubiquitinated by the BCR(KCTD13) and BCR(TNFAIP1) E3 ubiquitin ligase complexes, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and synaptic transmission in neurons.PTM Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling (By similarity). Phosphorylation by SLK at Ser-188 in response to AGTR2 activation (By similarity).PTM Serotonylation of Gln-63 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt Q9QUI0 1 EQUAL 190 EQUAL Reactome Database ID Release 78 5625902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5625902 Reactome R-MMU-5625902 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5625902.1 PIP3:RhoA Reactome DB_ID: 9771421 1 1 Reactome Database ID Release 78 9771421 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771421 Reactome R-MMU-202676 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-202676.1 Reactome Database ID Release 78 9771423 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771423 Reactome R-MMU-202692 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-202692.1 Several guanine exchange factors (GEFs) for the Rho family of GTPases contain PH domains that bind to PIP3. RhoA protein activation is a mechanism whereby PI3K acts independently of AKT (Chong et al. 1994, Oude Weernink et al. 1997). 23669310 Pubmed 2013 Signaling networks of Rho GTPases in cell motility Hanna, Samer El-Sibai, Mirvat Cell. Signal. 25:1955-61 7954816 Pubmed 1994 The small GTP-binding protein Rho regulates a phosphatidylinositol 4-phosphate 5-kinase in mammalian cells Chong, L D Traynor-Kaplan, A Bokoch, G M Schwartz, M A Cell 79:507-13 17245604 Pubmed 2007 Phospholipase D signaling: orchestration by PIP2 and small GTPases Oude Weernink, PA López de Jesús, M Schmidt, M Naunyn Schmiedebergs Arch Pharmacol 374:399-411 Reactome Database ID Release 78 9861214 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861214 Reactome R-MMU-198203 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198203.1 GENE ONTOLOGY GO:0048015 PI3K/AKT signalling is a major regulator of neuron survival. It blocks cell death by both impinging on the cytoplasmic cell death machinery and by regulating the expression of genes involved in cell death and survival. In addition, it may also use metabolic pathways to regulate cell survival.The PI3K/AKT pathway also affects axon diameter and branching (Marcus et al, 2002) and regulates small G proteins like RhoA (Vanhaesebroeck, B and Waterman, MD, 1999), which control the behaviour of the F-actin cytoskeleton. Moreover, through its connection with the TOR pathway, it promotes translation of a subset of mRNAs. 10579926 Pubmed 1999 Signaling by distinct classes of phosphoinositide 3-kinases Vanhaesebroeck, B Waterfield, MD Exp Cell Res 253:239-54 12123609 Pubmed 2002 Raf and akt mediate distinct aspects of sensory axon growth Markus, A Zhong, J Snider, WD Neuron 35:65-76 Signalling to ERK5 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT ERK5 translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Q9WVS8 phospho-Mapk7 p-T218,Y220-MAPK7 Reactome DB_ID: 9769083 UniProt:Q9WVS8 Mapk7 UniProt Q9WVS8 218 EQUAL 220 EQUAL 2 EQUAL 816 EQUAL Reactome Database ID Release 78 9769083 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769083 Reactome R-MMU-198721 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198721.1 Q9WVS8 phospho-Mapk7 p-T218,Y220-MAPK7 Reactome DB_ID: 9769085 2 EQUAL 816 EQUAL Reactome Database ID Release 78 9769085 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769085 Reactome R-MMU-198738 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198738.1 Reactome Database ID Release 78 9769087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769087 Reactome R-MMU-198714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198714.1 On phosphorylation, ERK5 translocates to the nucleus (Watson et al. 2001). 11544482 Pubmed 2001 Neurotrophins use the Erk5 pathway to mediate a retrograde survival response Watson, FL Heerssen, HM Bhattacharyya, A Klesse, L Lin, MZ Segal, RA Nat Neurosci 4:981-8 Reactome Database ID Release 78 9861240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861240 Reactome R-MMU-198765 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198765.1 The location of neurotrophin stimulation appears to determine the nature of the transcriptional response through differential uses of individual MAP kinases. The ERK5 pathway has a unique function in retrograde signalling; in contrast, ERK1/2, which mediate nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Following neurotrophin stimulation of distal axons, phosphorylated TRK receptors are endocytosed and transported to the cell bodies, where MEK5 phosphorylates ERK5, leading to ERK5 nuclear translocation, phosphorylation of transcription factors, and neuronal survival. In contrast, neurotrophin stimulation of the cell bodies causes concurrent activation and nuclear transport of ERK1/2 as well as ERK5. Several distinctive features of the ERK5 pathway might be important for retrograde signalling. The ERK5 cascade does not depend on activation of the G-protein RAS. Instead, this pathway may use other G-proteins such as RAP that are associated with vesicles, or may not require any G-protein intermediate. Another distinctive feature is that the MEK5 isoform, which is expressed in the nervous system, exhibits a punctate staining pattern, suggesting a vesicular localization. ERK5 itself significantly differs from ERK1/2, and its substrate specificity also differs from ERK1/2. For instance, ERK5 directly activates transcription factors, including MEF2, that are not phosphorylated by ERK1/2. Conversely, ERK1/2, but not ERK5, activate transcription factors such as ELK1 and MITF. Retrograde neurotrophin signalling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Axonal transport of NGF:Trk complexes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Activated TrkA receptor complex:Clathrin-coated vesicle:Endophilin Reactome DB_ID: 9766201 Sh3gl2 SH3GL2 Q62420 Reactome DB_ID: 9766199 UniProt:Q62420 Sh3gl2 UniProt Q62420 1 EQUAL 352 EQUAL Reactome Database ID Release 78 9766199 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766199 Reactome R-MMU-177495 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177495.1 1 1 Clathrin:AP-2 complex Reactome DB_ID: 9766195 Clathrin Reactome DB_ID: 9766193 Clta CLTA O08585 Reactome DB_ID: 9766187 UniProt:O08585 Clta UniProt O08585 1 EQUAL 248 EQUAL Reactome Database ID Release 78 9766187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766187 Reactome R-MMU-2980611 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2980611.1 3 Cltc CLTC Q68FD5 Reactome DB_ID: 9766191 UniProt:Q68FD5 Cltc UniProt Q68FD5 2 EQUAL 1675 EQUAL Reactome Database ID Release 78 9766191 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766191 Reactome R-MMU-2980668 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2980668.1 3 Reactome Database ID Release 78 9766193 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766193 Reactome R-MMU-177482 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177482.1 1 AP-2 complex Reactome DB_ID: 9766183 Ap2b1 AP2B1 Q9DBG3 Reactome DB_ID: 9766163 UniProt:Q9DBG3 Ap2b1 UniProt Q9DBG3 1 EQUAL 937 EQUAL Reactome Database ID Release 78 9766163 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766163 Reactome R-MMU-167690 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167690.1 1 Ap2s1 AP2S1 P62743 Reactome DB_ID: 9766171 UniProt:P62743 Ap2s1 UniProt P62743 1 EQUAL 142 EQUAL Reactome Database ID Release 78 9766171 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766171 Reactome R-MMU-389382 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-389382.1 1 Ap2m1 AP2M1 P84091 Reactome DB_ID: 9766167 UniProt:P84091 Ap2m1 UniProt P84091 1 EQUAL 435 EQUAL Reactome Database ID Release 78 9766167 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766167 Reactome R-MMU-167585 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167585.1 1 Converted from EntitySet in Reactome Adaptor protein complex 2 (AP-2) large adaptins Reactome DB_ID: 9766181 Ap2a1 AP2A1 P17426 Reactome DB_ID: 9766175 UniProt:P17426 Ap2a1 UniProt P17426 1 EQUAL 977 EQUAL Reactome Database ID Release 78 9766175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766175 Reactome R-MMU-177494 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177494.1 Ap2a2 AP2A2(1-939) P17427 Reactome DB_ID: 9766179 UniProt:P17427 Ap2a2 UniProt P17427 1 EQUAL 939 EQUAL Reactome Database ID Release 78 9766179 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766179 Reactome R-MMU-177502 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177502.1 Reactome Database ID Release 78 9766181 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766181 Reactome R-MMU-444999 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-444999.1 1 Reactome Database ID Release 78 9766183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766183 Reactome R-MMU-177480 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177480.1 1 Reactome Database ID Release 78 9766195 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766195 Reactome R-MMU-177505 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177505.1 1 Reactome Database ID Release 78 9766201 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766201 Reactome R-MMU-177490 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177490.1 ACTIVATION Dnal4 DNAL4 Q9DCM4 Reactome DB_ID: 9766205 UniProt:Q9DCM4 Dnal4 UniProt Q9DCM4 1 EQUAL 105 EQUAL Reactome Database ID Release 78 9766205 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766205 Reactome R-MMU-177484 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177484.1 GENE ONTOLOGY GO:0003777 Reactome Database ID Release 78 9766206 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766206 Reactome Database ID Release 78 9766208 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9766208 Reactome R-MMU-177479 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177479.1 GENE ONTOLOGY GO:0007018 Of the internalized NGF:TRK complexes, many undergo recycling and/or proteolysis. Only a small fraction is retrogradely transported. Vesicles containing neurotrophin, activated receptors and downstream kinases are transported through axons by the action of dynein, which produces a force towards the end of microtubules. 11157096 Pubmed 2001 Association of Trk neurotrophin receptors with components of the cytoplasmic dynein motor Yano, H Lee, FS Kong, H Chuang, J Arevalo, JC Perez, P Sung, C Chao, MV J Neurosci 21:RC125 Reactome Database ID Release 78 9861008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861008 Reactome R-MMU-177504 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-177504.1 Neurotrophin-TRK complexes can be internalized and enter signalling vesicles, which travel retrogradely over long distances from distal nerve terminals to neuronal cell bodies. Such retrograde signalling by neurotrophin-TRK complexes regulates survival, synaptogenesis and maintenance of proper neural connectivity. The neurotrophin-TRK complex may use three distinct internalization pathways. Although Clathrin-mediated endocytosys appears to be the major internalization route, it is controversial whether it also represents the dominant pathway for retrograde transport and signalling. Pyncher-mediated endocytosis might be more relevant in this regard. Moreover, also caveolin-mediated endocytosis may play a role in NGF-TrkA internalization.<br>Retrograde transport of TRKs is microtubule-dependent: TRKs remain activated and bound to neurotrophins during retrograde transport. The current view is reflected in the signalling endosome model. It is a specialized vesicle containing ligand (NGF, BDNF) bound to its activated TRK receptor, together with activated downstream signalling proteins, transported by motor proteins (dyneins) from nerve terminals to remote cell bodies, where the receptors trigger signalling cascades. Nuclear Events (kinase and transcription factor activation) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ERK/MAPK targets This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.11 ERK1/2 phosphorylates MSK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Q8C050 Rps6ka5 RPS6KA5 Reactome DB_ID: 9769068 UniProt:Q8C050 Rps6ka5 UniProt Q8C050 1 EQUAL 802 EQUAL Reactome Database ID Release 78 9769068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769068 Reactome R-MMU-198657 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198657.1 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 Reactome Database ID Release 78 29358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29358 Reactome R-ALL-29358 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29358.3 COMPOUND C00002 4 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 Reactome Database ID Release 78 113582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113582 Reactome R-ALL-113582 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113582.3 COMPOUND C00008 4 Q8C050 phospho-Rps6ka5 p-S212,S360,S376,T581-RPS6KA5 Reactome DB_ID: 9769074 376 EQUAL 581 EQUAL 360 EQUAL 212 EQUAL 1 EQUAL 802 EQUAL Reactome Database ID Release 78 9769074 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769074 Reactome R-MMU-198683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198683.1 ACTIVATION Reactome Database ID Release 78 9769092 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769092 Reactome Database ID Release 78 9769094 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769094 Reactome R-MMU-198756 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198756.1 MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by ERK1/2 through phosphorylation at four key residues. 9687510 Pubmed 1998 Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB Deak, M Clifton, AD Lucocq, LM Alessi, DR EMBO J 17:4426-41 LEFT-TO-RIGHT 2.7.11 p38MAPK phosphorylates MSK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 4 4 ACTIVATION Converted from EntitySet in Reactome p-MAPK11/p-MAPK14 p-p38 MAPK alpha/beta Phospho-MAP kinase p38 alpha/beta Reactome DB_ID: 9763880 p-T180,Y182-Mapk11 phospho-MAP kinase p38 beta Reactome DB_ID: 1605427 1 EQUAL 364 EQUAL Reactome Database ID Release 78 1605427 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1605427 Reactome R-MMU-1605427 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1605427.1 p-T180,Y182-Mapk14 phospho-MAP kinase p38 alpha Reactome DB_ID: 1605486 2 EQUAL 360 EQUAL Reactome Database ID Release 78 1605486 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1605486 Reactome R-MMU-1605486 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1605486.1 Reactome Database ID Release 78 9763880 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9763880 Reactome R-MMU-198703 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198703.1 Reactome Database ID Release 78 9769075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769075 Reactome Database ID Release 78 9769077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9769077 Reactome R-MMU-198669 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198669.1 MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by p38MAPK through phosphorylation at four key residues.<br> LEFT-TO-RIGHT 3.1.3.16 ERKs are inactivated by protein phosphatase 2A This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> H2O water Reactome DB_ID: 113518 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 78 113518 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113518 Reactome R-ALL-113518 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113518.3 COMPOUND C00001 Converted from EntitySet in Reactome p-ERK1/2/5 dimers p-MAPK3/MAPK1/MAPK7 dimers Reactome DB_ID: 9770136 p-T1218, Y220 MAPK7 dimer Reactome DB_ID: 9770134 2 Reactome Database ID Release 78 9770134 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770134 Reactome R-MMU-9610768 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610768.1 Reactome Database ID Release 78 9770136 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770136 Reactome R-MMU-199878 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199878.1 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 113550 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 78 113550 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113550 Reactome R-ALL-113550 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113550.4 COMPOUND C00009 Converted from EntitySet in Reactome ERK1/2/5 MAPK3/MAPK1/MAPK7 dimers Reactome DB_ID: 9770150 MAPK1 dimer Reactome DB_ID: 9770140 Mapk1 MAPK1 P63085 Reactome DB_ID: 9770138 2 EQUAL 360 EQUAL Reactome Database ID Release 78 9770138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770138 Reactome R-MMU-199960 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199960.1 2 Reactome Database ID Release 78 9770140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770140 Reactome R-MMU-5675356 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5675356.1 MAPK3 dimer Reactome DB_ID: 9770144 Mapk3 MAPK3 Q63844 Reactome DB_ID: 9770142 2 EQUAL 379 EQUAL Reactome Database ID Release 78 9770142 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770142 Reactome R-MMU-73724 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-73724.1 2 Reactome Database ID Release 78 9770144 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770144 Reactome R-MMU-5675359 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5675359.1 MAPK7 dimer Reactome DB_ID: 9770148 Mapk7 MAPK7 Q9WVS8 Reactome DB_ID: 9770146 2 EQUAL 816 EQUAL Reactome Database ID Release 78 9770146 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770146 Reactome R-MMU-199961 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199961.1 2 Reactome Database ID Release 78 9770148 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770148 Reactome R-MMU-9610770 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9610770.1 Reactome Database ID Release 78 9770150 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770150 Reactome R-MMU-199955 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199955.1 ACTIVATION PP2A-ABdeltaC complex Reactome DB_ID: 9770154 Converted from EntitySet in Reactome PP2A-subunit A Reactome DB_ID: 9759423 Q76MZ3 Ppp2r1a PPP2R1A Reactome DB_ID: 9759417 UniProt:Q76MZ3 Ppp2r1a Ppp2r1a FUNCTION The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit (PubMed:10100624). Upon interaction with GNA12 promotes dephosphorylation of microtubule associated protein TAU/MAPT (By similarity). Required for proper chromosome segregation and for centromeric localization of SGO1 in mitosis (By similarity).SUBUNIT PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD (By similarity). Interacts with FOXO1; the interaction dephosphorylates FOXO1 on AKT-mediated phosphorylation sites (PubMed:22417654). Interacts with IPO9 (By similarity). Interacts with TP53 and SGO1 (By similarity). Interacts with PLA2G16; this interaction might decrease PP2A activity (By similarity). Interacts with CTTNBP2NL (By similarity). Interacts with GNA12; the interaction promotes protein phosphatase 2A activation causing dephosphorylation of MAPT (By similarity).Interacts with CIP2A; this interaction stabilizes CIP2A (By similarity). Interacts with PABIR1/FAM122A (By similarity). Interacts with ADCY8; antagonizes interaction between ADCY8 and calmodulin (PubMed:16258073). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118). Interacts with SPRY2 (By similarity).DOMAIN Each HEAT repeat appears to consist of two alpha helices joined by a hydrophilic region, the intrarepeat loop. The repeat units may be arranged laterally to form a rod-like structure.SIMILARITY Belongs to the phosphatase 2A regulatory subunit A family. UniProt Q76MZ3 2 EQUAL 589 EQUAL Reactome Database ID Release 78 9759417 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759417 Reactome R-MMU-165968 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-165968.1 Q7TNP2 Ppp2r1b PPP2R1B Reactome DB_ID: 9759421 UniProt:Q7TNP2 Ppp2r1b UniProt Q7TNP2 1 EQUAL 601 EQUAL Reactome Database ID Release 78 9759421 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759421 Reactome R-MMU-166000 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-166000.1 Reactome Database ID Release 78 9759423 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759423 Reactome R-MMU-165997 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-165997.1 1 Q7TNL5 Ppp2r5d PPP2R5D Reactome DB_ID: 9770152 UniProt:Q7TNL5 Ppp2r5d UniProt Q7TNL5 1 EQUAL 602 EQUAL Reactome Database ID Release 78 9770152 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770152 Reactome R-MMU-3008956 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-3008956.1 1 Converted from EntitySet in Reactome PP2A-catalytic subunit C Reactome DB_ID: 9759414 Ppp2ca PPP2CA P63330 Reactome DB_ID: 9759409 UniProt:P63330 Ppp2ca UniProt P63330 1 EQUAL 309 EQUAL Reactome Database ID Release 78 9759409 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759409 Reactome R-MMU-165978 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-165978.1 Ppp2cb PPP2CB P62715 Reactome DB_ID: 9759412 UniProt:P62715 Ppp2cb Ppp2cb FUNCTION PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase.SUBUNIT PP2A consists of a common heterodimeric core enzyme (composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65) (subunit A)) that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Binds PPME1. May indirectly interact with SGO1, most probably through regulatory B56 subunits. Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD. Interacts with TBCD. Interacts with CTTNBP2NL. Interacts with PTPA.PTM Reversibly methyl esterified on Leu-309 by leucine carboxyl methyltransferase 1 (Lcmt1) and protein phosphatase methylesterase 1 (Ppme1). Carboxyl methylation influences the affinity of the catalytic subunit for the different regulatory subunits, thereby modulating the PP2A holoenzyme's substrate specificity, enzyme activity and cellular localization (By similarity).PTM Phosphorylation of either threonine (by autophosphorylation-activated protein kinase) or tyrosine results in inactivation of the phosphatase. Auto-dephosphorylation has been suggested as a mechanism for reactivation (By similarity).PTM May be monoubiquitinated by NOSIP.SIMILARITY Belongs to the PPP phosphatase family. PP-1 subfamily. UniProt P62715 1 EQUAL 309 EQUAL Reactome Database ID Release 78 9759412 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759412 Reactome R-MMU-165991 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-165991.1 Reactome Database ID Release 78 9759414 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759414 Reactome R-MMU-165974 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-165974.1 1 Reactome Database ID Release 78 9770154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770154 Reactome R-MMU-165970 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-165970.1 GENE ONTOLOGY GO:0004722 Reactome Database ID Release 78 9770155 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770155 Reactome Database ID Release 78 9770157 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770157 Reactome R-MMU-199959 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199959.1 ERKs are inactivated by the protein phosphatase 2A (PP2A). The PP2A holoenzyme is a heterotrimer that consists of a core dimer, composed of a scaffold (A) and a catalytic (C) subunit that associates with a variety of regulatory (B) subunits. The B subunits have been divided into gene families named B (or PR55), B0 (or B56 or PR61) and B00 (or PR72). Each family comprises several members. B56 family members of PP2A in particular, increase ERK dephosphorylation, without affecting its activation by MEK.<br>Induction of PP2A is involved in the extracellular signal-regulated kinase (ERK) signalling pathway, in which it provides a feedback control, as well as in a broad range of other cellular processes, including transcriptional regulation and control of the cell cycle.This diversity of functions is conferred by a diversity of regulatory subunits, the combination of which can give rise to over 50 different forms of PP2A. For example, five distinct mammalian genes encode members of the B56 family, called B56a, b, g, d and e, generating at least eight isoforms. Whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown. 16456541 Pubmed 2006 B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK Letourneux, C Rocher, G Porteu, F EMBO J 25:727-38 ERKs are inactivated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 3.1.3.48 ERKs are inactivated by dual-specific phosphatases (DUSPs) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ACTIVATION Converted from EntitySet in Reactome ERK-specific DUSP Reactome DB_ID: 9771801 Dusp3 DUSP3 Q9D7X3 Reactome DB_ID: 9771787 UniProt:Q9D7X3 Dusp3 UniProt Q9D7X3 1 EQUAL 185 EQUAL Reactome Database ID Release 78 9771787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771787 Reactome R-MMU-203798 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-203798.1 Dusp4 DUSP4 Q8BFV3 Reactome DB_ID: 9771791 UniProt:Q8BFV3 Dusp4 UniProt Q8BFV3 1 EQUAL 394 EQUAL Reactome Database ID Release 78 9771791 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771791 Reactome R-MMU-203794 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-203794.1 Dusp7 DUSP7 Q91Z46 Reactome DB_ID: 9771795 UniProt:Q91Z46 Dusp7 UniProt Q91Z46 1 EQUAL 419 EQUAL Reactome Database ID Release 78 9771795 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771795 Reactome R-MMU-203791 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-203791.1 Dusp6 DUSP6 Q9DBB1 Reactome DB_ID: 9771799 UniProt:Q9DBB1 Dusp6 UniProt Q9DBB1 1 EQUAL 381 EQUAL Reactome Database ID Release 78 9771799 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771799 Reactome R-MMU-2871619 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2871619.1 Reactome Database ID Release 78 9771801 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771801 Reactome R-MMU-203792 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-203792.1 GENE ONTOLOGY GO:0004725 Reactome Database ID Release 78 9771802 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771802 Reactome Database ID Release 78 9771810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771810 Reactome R-MMU-203797 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-203797.1 Over 10 dual specificity phosphatases (DUSPs) active on MAP kinases are known. Among them, some possess good ERK docking sites and so are more specific for the ERKS (DUSP 3, 4, 6, 7), others are more specific for p38MAPK (DUSP1 and 10), while others do not seem to discriminate. It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. Moreover, differential activation of DUSPs by different stimuli is thought to contribute to pathway specificity. 17322878 Pubmed 2007 A module of negative feedback regulators defines growth factor signaling Amit, I Citri, A Shay, T Lu, Y Katz, M Zhang, F Tarcic, G Siwak, D Lahad, J Jacob-Hirsch, J Amariglio, N Vaisman, N Segal, E Rechavi, G Alon, U Mills, GB Domany, E Yarden, Y Nat Genet 39:503-12 INHIBITION Reactome Database ID Release 78 9771811 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771811 VRK3:DUSP3 Reactome DB_ID: 9771808 1 Vrk3 VRK3 Q8K3G5 Reactome DB_ID: 9771806 UniProt:Q8K3G5 Vrk3 UniProt Q8K3G5 1 EQUAL 474 EQUAL Reactome Database ID Release 78 9771806 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771806 Reactome R-MMU-8942507 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8942507.1 1 Reactome Database ID Release 78 9771808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9771808 Reactome R-MMU-8942511 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8942511.1 Reactome Database ID Release 78 9861280 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861280 Reactome R-MMU-202670 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-202670.1 MAP Kinases are inactivated by a family of protein named MAP Kinase Phosphatases (MKPs). They act through dephosphorylation of threonine and/or tyrosine residues within the signature sequence -pTXpY- located in the activation loop of MAP kinases (pT=phosphothreonine and pY=phosphotyrosine). MKPs are divided into three major categories depending on their preference for dephosphorylating; tyrosine, serine/threonine and both the tyrosine and threonine (dual specificity phoshatases or DUSPs). The tyrosine-specific MKPs include PTP-SL, STEP and HePTP, serine/threonine-specific MKPs are PP2A and PP2C, and many DUSPs acting on MAPKs are known. Activated MAP kinases trigger activation of transcription of MKP genes. Therefore, MKPs provide a negative feedback regulatory mechanism on MAPK signaling, by inactivating MAPKs via dephosphorylation, in the cytoplasm and the nucleus. Some MKPs are more specific for ERKs, others for JNK or p38MAPK. 15115656 Pubmed 2004 Structure and regulation of MAPK phosphatases Farooq, A Zhou, MM Cell Signal 16:769-79 Reactome Database ID Release 78 9861236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861236 Reactome R-MMU-198753 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198753.1 ERK/MAPK kinases have a number of targets within the nucleus, usually transcription factors or other kinases. The best known targets, ELK1, ETS1, ATF2, MITF, MAPKAPK2, MSK1, RSK1/2/3 and MEF2 are annotated here. CREB phosphorylation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.11 MSK1 activates CREB This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Creb1 Reactome DB_ID: 9021874 UniProt:Q01147 Creb1 Creb1 Creb-1 FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. Interacts (phosphorylated form) with TOX3 (By similarity). When phosphorylated on Ser-119, binds CREBBP. Interacts with ARRB1. Binds to HIPK2 (By similarity). Interacts with SGK1 (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (By similarity). Forms a complex with KMT2A and CREBBP (By similarity).TISSUE SPECIFICITY Ubiquitously expressed.PTM Phosphorylation of Ser-119 allows CREBBP binding. Stimulated by phosphorylation. Phosphorylated Ser-128 can be detected in the suprachiasmatic nucleus (SCN), the amygdala, the cortex, and the hippocampus but not in the striatum nor in the cerebellum. In the SCN, phosphorylation of Ser-128 and Ser-119 are stimulated by light exposure and submitted to circadian oscillations. In the retina, only phosphorylation of Ser-119 can be detected upon light exposure. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CAMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1. Phosphorylation of Ser-271 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP (By similarity). Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion. Phosphorylated by TSSK4 on Ser-119 (By similarity).PTM Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization (By similarity).SIMILARITY Belongs to the bZIP family. UniProt Q01147 1 EQUAL 341 EQUAL Reactome Database ID Release 78 9021874 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9021874 Reactome R-MMU-9021874 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9021874.1 p-S133-Creb1 Reactome DB_ID: 2976548 133 EQUAL 1 EQUAL 341 EQUAL Reactome Database ID Release 78 2976548 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2976548 Reactome R-MMU-2976548 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2976548.1 ACTIVATION Reactome Database ID Release 78 9770123 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770123 Reactome Database ID Release 78 9770132 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770132 Reactome R-MMU-199935 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199935.1 MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB). LEFT-TO-RIGHT 2.7.11 MSK1 activates ATF1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Atf1 ATF1 P81269 Reactome DB_ID: 9770119 UniProt:P81269 Atf1 UniProt P81269 1 EQUAL 271 EQUAL Reactome Database ID Release 78 9770119 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770119 Reactome R-MMU-199900 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199900.1 P81269 phospho-Atf1 p-S63-ATF1 Reactome DB_ID: 9770122 63 EQUAL 1 EQUAL 271 EQUAL Reactome Database ID Release 78 9770122 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770122 Reactome R-MMU-199897 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199897.1 ACTIVATION Reactome Database ID Release 78 9770125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770125 Reactome R-MMU-199910 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199910.1 Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it. 12414794 Pubmed 2002 ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expression Gupta, Pankaj Prywes, Ron J. Biol. Chem. 277:50550-6 LEFT-TO-RIGHT 2.7.11 MAPKAPK2 phosphorylates CREB at Serine 133 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ACTIVATION P49138 phospho-Mapkapk2 p-T222,S272-MAPKAPK2 Reactome DB_ID: 9770127 1 EQUAL 400 EQUAL Reactome Database ID Release 78 9770127 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770127 Reactome R-MMU-199936 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199936.1 Reactome Database ID Release 78 9770128 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770128 Reactome Database ID Release 78 9770130 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9770130 Reactome R-MMU-199917 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199917.1 p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3. 7551568 Pubmed 1995 Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals Bonni, A Ginty, D D Dudek, H Greenberg, M E Mol. Cell. Neurosci. 6:168-83 Reactome Database ID Release 78 9861278 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861278 Reactome R-MMU-199920 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-199920.1 Nerve growth factor (NGF) activates multiple signalling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133. CREB phosphorylation at serine 133 is a crucial event in neurotrophin signalling, being mediated by ERK/RSK, ERK/MSK1 and p38/MAPKAPK2 pathways. Several kinases, such as MSK1, RSK1/2/3 (MAPKAPK1A/B/C), and MAPKAPK2, are able to directly phosphorylate CREB at S133. MSK1 is also able to activate ATF (Cyclic-AMP-dependent transcription factor). However, the NGF-induced CREB phosphorylation appears to correlate better with activation of MSK1 rather than RSK1/2/3, or MAPKAPK2. In retrograde signalling, activation of CREB occurs within 20 minutes after neurotrophin stimulation of distal axons. NGF-stimulated transcription This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.11 SGK phosphorylates CREB1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ACTIVATION Q9WVC6 phospho-Sgk1 p-T256,S422-SGK1 Reactome DB_ID: 9856791 UniProt:Q9WVC6 Sgk1 Sgk1 Sgk FUNCTION Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cellular enzymes, transcription factors, neuronal excitability, cell growth, proliferation, survival, migration and apoptosis. Plays an important role in cellular stress response. Contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Up-regulates Na(+) channels: SCNN1A/ENAC, SCN5A and ASIC1/ACCN2, K(+) channels: KCNJ1/ROMK1, KCNA1-5, KCNQ1-5 and KCNE1, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channels: BSND, CLCN2 and CFTR, glutamate transporters: SLC1A3/EAAT1, SLC1A2 /EAAT2, SLC1A1/EAAT3, SLC1A6/EAAT4 and SLC1A7/EAAT5, amino acid transporters: SLC1A5/ASCT2, SLC38A1/SN1 and SLC6A19, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, glutamate receptor: GRIK2/GLUR6. Up-regulates carriers: SLC9A3/NHE3, SLC12A1/NKCC2, SLC12A3/NCC, SLC5A3/SMIT, SLC2A1/GLUT1, SLC5A1/SGLT1 and SLC15A2/PEPT2. Regulates enzymes: GSK3A/B, PMM2 and Na(+)/K(+) ATPase, and transcription factors: CTNNB1 and nuclear factor NF-kappa-B. Stimulates sodium transport into epithelial cells by enhancing the stability and expression of SCNN1A/ENAC. This is achieved by phosphorylating the NEDD4L ubiquitin E3 ligase, promoting its interaction with 14-3-3 proteins, thereby preventing it from binding to SCNN1A/ENAC and targeting it for degradation. Regulates store-operated Ca(+2) entry (SOCE) by stimulating ORAI1 and STIM1. Regulates KCNJ1/ROMK1 directly via its phosphorylation or indirectly via increased interaction with SLC9A3R2/NHERF2. Phosphorylates MDM2 and activates MDM2-dependent ubiquitination of p53/TP53. Phosphorylates MAPT/TAU and mediates microtubule depolymerization and neurite formation in hippocampal neurons. Phosphorylates SLC2A4/GLUT4 and up-regulates its activity. Phosphorylates APBB1/FE65 and promotes its localization to the nucleus. Phosphorylates MAPK1/ERK2 and activates it by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Phosphorylates FBXW7 and plays an inhibitory role in the NOTCH1 signaling. Phosphorylates FOXO1 resulting in its relocalization from the nucleus to the cytoplasm. Phosphorylates FOXO3, promoting its exit from the nucleus and interference with FOXO3-dependent transcription. Phosphorylates BRAF and MAP3K3/MEKK3 and inhibits their activity. Phosphorylates SLC9A3/NHE3 in response to dexamethasone, resulting in its activation and increased localization at the cell membrane. Phosphorylates CREB1. Necessary for vascular remodeling during angiogenesis.ACTIVITY REGULATION Two specific sites, one in the kinase domain (Thr-256) and the other in the C-terminal regulatory region (Ser-422), need to be phosphorylated for its full activation. Phosphorylation at Ser-397 and Ser-401 are also essential for its activity. Activated by WNK1, WNK2, WNK3 and WNK4.SUBUNIT Homodimer; disulfide-linked. Interacts with MAPK3/ERK1, MAPK1/ERK2, MAP2K1/MEK1, MAP2K2/MEK2, NEDD4, NEDD4L, MAPT/TAU, MAPK7, CREB1, SLC9A3R2/NHERF2 and KCNJ1/ROMK1 (By similarity). Forms a trimeric complex with FBXW7 and NOTCH1 Associates with the mammalian target of rapamycin complex 2 (mTORC2) via an interaction with MAPKAP1/SIN1.INDUCTION Up-regulated by tumor suppressor p53 in mammary epithelial tumor cells.PTM Regulated by phosphorylation. Activated by phosphorylation on Ser-422 by mTORC2, transforming it into a substrate for PDPK1 which phosphorylates it on Thr-256. Phosphorylation on Ser-397 and Ser-401 are also essential for its activity. Phosphorylation on Ser-78 by MAPK7 is required for growth factor-induced cell cycle progression (By similarity).PTM Ubiquitinated by NEDD4L; which promotes proteasomal degradation. Ubiquitinated by SYVN1 at the endoplasmic reticulum; which promotes rapid proteasomal degradation and maintains a high turnover rate in resting cells (By similarity).SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. UniProt Q9WVC6 422 EQUAL 256 EQUAL 1 EQUAL 431 EQUAL Reactome Database ID Release 78 9856791 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856791 Reactome R-MMU-9612512 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9612512.1 Reactome Database ID Release 78 9856792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856792 Reactome Database ID Release 78 9856794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856794 Reactome R-MMU-9612501 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9612501.1 Serum/glucocorticoid-induced kinase (SGK) phosphorylates CREB1 at S133 downstream of mutiple cellular stimuli (Lee et al, 1995; David et al, 2005). SGK activity contributes to EGR1 gene expression by promoting the phosphorylation of CREB1 and SRF transcription factor, both of which have binding sites in the EGR1 promoter (Tyan et al, 2008; Sakomoto et al, 1991; Schwachtgen et al, 2000). 18088355 Pubmed 2008 Serum- and glucocorticoid-inducible kinase 1 enhances zif268 expression through the mediation of SRF and CREB1 associated with spatial memory formation Tyan, Shiaw-Wei Tsai, Ming-Chi Lin, Chien-Ling Ma, Yun-Li Lee, Eminy H Y J. Neurochem. 105:820-32 15733869 Pubmed 2005 Serum/glucocorticoid-inducible kinase can phosphorylate the cyclic AMP response element binding protein, CREB David, Samuel Kalb, Robert G FEBS Lett. 579:1534-8 7608156 Pubmed 1995 Transcriptional activation of egr-1 by granulocyte-macrophage colony-stimulating factor but not interleukin 3 requires phosphorylation of cAMP response element-binding protein (CREB) on serine 133 Lee, Hu-Jung Mignacca, Robert C Sakamoto, Kathleen M J. Biol. Chem. 270:15979-83 2052361 Pubmed 1991 5' upstream sequence and genomic structure of the human primary response gene, EGR-1/TIS8 Sakamoto, Kathleen M Bardeleben, C Yates, K E Raines, M A Golde, D W Gasson, J C Oncogene 6:867-71 10826704 Pubmed 2000 Full promoter sequence of human early growth response factor-1 (Egr-1): demonstration of a fifth functional serum response element Schwachtgen, J L Campbell, C J Braddock, M DNA Seq. 10:429-32 LEFT-TO-RIGHT 2.7.11 SGK phosphorylates SRF This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Srf SRF Q9JM73 Reactome DB_ID: 9827388 UniProt:Q9JM73 Srf Srf FUNCTION SRF is a transcription factor that binds to the serum response element (SRE), a short sequence of dyad symmetry located 300 bp to the 5' of the site of transcription initiation of some genes (such as FOS) (PubMed:24732378). Together with MRTFA transcription coactivator, controls expression of genes regulating the cytoskeleton during development, morphogenesis and cell migration (PubMed:12732141, PubMed:19350017, PubMed:24732378). The SRF-MRTFA complex activity responds to Rho GTPase-induced changes in cellular globular actin (G-actin) concentration, thereby coupling cytoskeletal gene expression to cytoskeletal dynamics (PubMed:24732378). Required for cardiac differentiation and maturation (PubMed:15169892).SUBUNIT Binds DNA as a multimer, probably a dimer (PubMed:15492011, PubMed:16782067). Interacts with MRTFA, forming the SRF-MRTFA nuclear complex which binds the 5'-CArG-3' consensus motif (CArG box) on DNA via SRF (PubMed:12732141, PubMed:19350017). Forms a nuclear ternary complex with MRTFA and SCAI (PubMed:19350017). Interacts with MRTFB (By similarity). Interacts with MLLT7/FOXO4, NKX3A and SSRP1 (By similarity). Interacts with ARID2 (PubMed:16782067). Interacts with SRFBP1 (PubMed:15492011). Interacts with FOXK1 (By similarity). Interacts with LPXN (By similarity). Interacts with OLFM2; the interaction promotes dissociation of SRF from the transcriptional repressor HEY2, facilitates binding of SRF to target genes and promotes smooth muscle differentiation (By similarity).PTM Phosphorylated by PRKDC.DISRUPTION PHENOTYPE Mice lacking Srf in cardiac tissue display lethal cardiac defects between E10.5 and E13.5 characterized by abnormally thin myocardium, dilated cardiac chambers, poor trabeculation and a disorganised interventricular septum. UniProt Q9JM73 1 EQUAL 508 EQUAL Reactome Database ID Release 78 9827388 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827388 Reactome R-MMU-5666000 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5666000.1 Q9JM73 phospho-Srf p-S103 SRF Reactome DB_ID: 9856797 103 EQUAL 1 EQUAL 508 EQUAL Reactome Database ID Release 78 9856797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856797 Reactome R-MMU-9612518 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9612518.1 ACTIVATION Reactome Database ID Release 78 9856799 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856799 Reactome R-MMU-9612509 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9612509.1 Serum/glucticocorticoid kinase (SGK) phosphorylates SRF at serine residue 103 in response to multiple upstream stimuli (Tyan et al, 2008). Phosphorylation of SRF and CREB1 by SGK contributes to the SGK-dependent expression of EGR1, an immediate early gene with roles in neuronal development, (David et al, 2005; Tyan et al, 2008; reviewed in Pagel and Deindl, 2011). 22053691 Pubmed 2011 Early growth response 1--a transcription factor in the crossfire of signal transduction cascades Pagel, Judith-Irina Deindl, Elisabeth Indian J. Biochem. Biophys. 48:226-35 LEFT-TO-RIGHT NAB2 and CHD4 bind and repress EGR-mediated RRAD gene expression This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Chd4 CHD4 Q6PDQ2 Reactome DB_ID: 9755400 UniProt:Q6PDQ2 Chd4 Chd4 FUNCTION Component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin by deacetylating histones.SUBUNIT Central component of the nucleosome remodeling and histone deacetylase (NuRD) repressor complex (PubMed:11003653). Interacts with KLF1; the interaction depends on sumoylation of KLF1, and leads to its transcriptional repression (PubMed:17938210). Interacts with ZGPAT; the interaction is direct. Interacts with BCL6, BRD4 and PCNT. Interacts directly with IKFZ1 in the NuRD complex. Interacts with TRIM27. Part of a complex containing ATR and HDAC2. Interacts with SETX (By similarity). Interacts with HDAC1 (By similarity).SIMILARITY Belongs to the SNF2/RAD54 helicase family. UniProt Q6PDQ2 1 EQUAL 1912 EQUAL Reactome Database ID Release 78 9755400 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9755400 Reactome R-MMU-3702078 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-3702078.1 RRAD gene:EGR2 Reactome DB_ID: 9856810 Ghost homologue of RRAD gene Reactome DB_ID: 9856808 Reactome Database ID Release 78 9856808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856808 Reactome R-MMU-9613162 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9613162.1 1 Egr2 EGR2 P08152 Reactome DB_ID: 9856806 UniProt:P08152 Egr2 Egr2 Egr-2 Krox-20 Zfp-25 FUNCTION Sequence-specific DNA-binding transcription factor (PubMed:1969796, PubMed:1674431, PubMed:11823429, PubMed:31852952). Plays a role in hindbrain segmentation by regulating the expression of a subset of homeobox containing genes and in Schwann cell myelination by regulating the expression of genes involved in the formation and maintenance of myelin (PubMed:1969796, PubMed:1674431, PubMed:11823429, PubMed:31852952, PubMed:8093858). Binds to two EGR2-consensus sites EGR2A (5'-CTGTAGGAG-3') and EGR2B (5'-ATGTAGGTG-3') in the HOXB3 enhancer and promotes HOXB3 transcriptional activation (PubMed:11823429). Binds to specific DNA sites located in the promoter region of HOXA4, HOXB2 and ERBB2 (PubMed:1969796, PubMed:8093858, PubMed:17938205). Regulates hindbrain segmentation by controlling the expression of Hox genes, such as HOXA4, HOXB3 and HOXB2, and thereby specifying odd and even rhombomeres (PubMed:11823429, PubMed:1674431). Promotes the expression of HOXB3 in the rhombomere r5 and of HOXB3 in r3 and r5 in the hindbrain (PubMed:11823429, PubMed:8093858). Regulates myelination in the peripheral nervous system after birth, possibly by regulating the expression of myelin proteins, such as MPZ, and by promoting the differentiation of Schwann cells (PubMed:7935840, PubMed:10068633). Involved in the development of the jaw openener musculature, probably by playing a role in its innervation through trigeminal motor neurons (PubMed:11509834). May play a role in adipogenesis, possibly by regulating the expression of CEBPB (PubMed:16054051).FUNCTION E3 SUMO-protein ligase helping SUMO1 conjugation to its coregulators NAB1 and NAB2, whose sumoylation down-regulates EGR2 transcriptional activity.PATHWAY Protein modification; protein sumoylation.SUBUNIT Interacts with HCFC1 (By similarity). Interacts with WWP2 (PubMed:19651900). Interacts with UBC9 (By similarity). Interacts with CITED1 (PubMed:17938205). Interacts (via phosphorylated form) with SFN (PubMed:17938205).TISSUE SPECIFICITY Expressed mainly in the thymus.DEVELOPMENTAL STAGE Before 8 dpc, expressed in the future rhombomere r3 at 0-3 somites, followed by expression in rhombomere r5 in 4-7 somites at 8 dpc, and maintained until 12 somites (PubMed:8093858). Expressed in migrating neural crest cells from r5/r6 (PubMed:8093858). Expressed in boundary cap cells that surround nerve exit points from the central nervous system at 10.5 dpc (PubMed:7935840, PubMed:8093858). Up to 14.5 dpc, expressed in motor and sensory roots of cranial and spinal nerves (PubMed:7935840). After 15.5 dpc, expressed in the entire peripheral nervous system (PubMed:7935840). Expressed in the embryonic nervous system (PubMed:17938205). Expressed in myelinating Schwann cells 2 weeks after birth (PubMed:7935840).INDUCTION Activated during G0/G1 transition in cultured cells.PTM Ubiquitinated by WWP2 leading to proteasomal degradation.PTM Acetylated at Lys-247. May be deacetylated by HDAC6, HDAC10 or SIRT1.DISRUPTION PHENOTYPE Failure to promote expression of the Hoxb3 reporter in rhombomere r5 in the hindbrain (PubMed:11823429). Changed morphology of the sciatic nerves, with a higher density of Schwann cells, and a reduction in major components of compacted myelin, including lipidic components, as well as myelin proteins Mpz and Mbp (PubMed:7935840). Schwann cells in the sciatic nerves exhibit increased expression of Scip, reduced expression of Mpz, elevated mitotic activity and increased apoptosis at postnatal day P12 (PubMed:10068633). Total absence of myelin along the axons of sciatic nerves at postnatal day P15 (PubMed:7935840). Does not seem to affect the myelination in the central nervous system (PubMed:7935840). Signs of atrophy in the jaw openener anterior digastric (AD) and mylohoid (MY) muscles at 15 dpc with smaller diameter fibers, fibers with triangular shape, increased amount of connective tissue surrounding the fibers, suggesting a lack of neural innervation (PubMed:11509834). Reduced volume of the delineated trigeminal motor nucleus and restructuring of the brainstem at 15 dpc (PubMed:11509834). Reduced volume in both AD and MY musculature and reduced milk indigestion after birth (PubMed:11509834).SIMILARITY Belongs to the EGR C2H2-type zinc-finger protein family. UniProt P08152 1 EQUAL 476 EQUAL Reactome Database ID Release 78 9856806 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856806 Reactome R-MMU-977385 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-977385.1 1 Reactome Database ID Release 78 9856810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856810 Reactome R-MMU-9613167 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9613167.1 Nab2 NAB2 Q61127 Reactome DB_ID: 9856803 UniProt:Q61127 Nab2 UniProt Q61127 1 EQUAL 585 EQUAL Reactome Database ID Release 78 9856803 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856803 Reactome R-MMU-9612177 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9612177.1 RRAD gene:EGR2:NAB2:CHD4 Reactome DB_ID: 9856812 1 1 1 1 Reactome Database ID Release 78 9856812 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856812 Reactome R-MMU-9613187 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9613187.1 Reactome Database ID Release 78 9856814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9856814 Reactome R-MMU-9613213 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9613213.1 NAB2 is recruited to EGR2 to the RRAD promoter through interaction with the NCD1 (NAB conserved domain 1) (Svaren et al, 1996; Svaren et al, 1998). NAB2 in turn recruits the CHD4 subunit of the NURD chromatin remodelling complex through its CID (CHD4-interacting domain) and in this manner, represses transcription from the RRAD promoter (Srinivasan et al, 2006; Mager et al, 2008). In addition to roles in cellular proliferation and cardiac function, RRAD protein is known to contribute to RHO signaling, which promotes Schwann cell migration and myelination (Zhu et al, 1999; Wang et al, 2010; Chang et al, 2007, Ward et al, 2002; Yamauchi et al, 2004; Melendez-Vasquez et al, 2004). 19926875 Pubmed 2010 Rad as a novel regulator of excitation-contraction coupling and beta-adrenergic signaling in heart Wang, Gang Zhu, Xiaojun Xie, Wenjun Han, Peidong Li, Kaitao Sun, Zhongcui Wang, Yanru Chen, Chunlei Song, Ruisheng Cao, Chunmei Zhang, Jifeng Wu, Caihong Liu, Jie Cheng, Heping Circ. Res. 106:317-27 9418898 Pubmed 1998 Nab1, a corepressor of NGFI-A (Egr-1), contains an active transcriptional repression domain Swirnoff, Alexander H Apel, Elizabeth D Svaren, John Sevetson, Bradley R Zimonjic, Drazen B Popescu, Nicholas C Milbrandt, Jeffrey Mol. Cell. Biol. 18:512-24 8668170 Pubmed 1996 NAB2, a corepressor of NGFI-A (Egr-1) and Krox20, is induced by proliferative and differentiative stimuli Svaren, John Sevetson, Bradley R Apel, Elizabeth D Zimonjic, Drazen B Popescu, Nicholas C Milbrandt, Jeffrey Mol. Cell. Biol. 16:3545-53 15102911 Pubmed 2004 Rho kinase regulates schwann cell myelination and formation of associated axonal domains Melendez-Vasquez, Carmen V Einheber, Steven Salzer, James L J. Neurosci. 24:3953-63 10611312 Pubmed 1999 Interaction of the Ras-related protein associated with diabetes rad and the putative tumor metastasis suppressor NM23 provides a novel mechanism of GTPase regulation Zhu, Jianhua Tseng, Yu-Hua Kantor, Jason D Rhodes, Christopher J Zetter, Bruce R Moyers, Julie S Kahn, C Ronald Proc. Natl. Acad. Sci. U.S.A. 96:14911-8 15161978 Pubmed 2004 Neurotrophins regulate Schwann cell migration by activating divergent signaling pathways dependent on Rho GTPases Yamauchi, Junji Chan, Jonah R Shooter, Eric M Proc. Natl. Acad. Sci. U.S.A. 101:8774-9 18456662 Pubmed 2008 Active gene repression by the Egr2.NAB complex during peripheral nerve myelination Mager, Gennifer M Ward, Rebecca M Srinivasan, Rajini Jang, Sung-Wook Wrabetz, Lawrence Svaren, John J. Biol. Chem. 283:18187-97 18056528 Pubmed 2007 Rad GTPase deficiency leads to cardiac hypertrophy Chang, Lin Zhang, Jifeng Tseng, Yu-Hua Xie, Chang-Qing Ilany, Jacob Brüning, Jens C Sun, Zhongcui Zhu, Xiaojun Cui, Taixing Youker, Keith A Yang, Qinglin Day, Sharlene M Kahn, C Ronald Chen, Y Eugene Circulation 116:2976-2983 16574654 Pubmed 2006 NAB2 represses transcription by interacting with the CHD4 subunit of the nucleosome remodeling and deacetylase (NuRD) complex Srinivasan, Rajini Mager, Gennifer M Ward, Rebecca M Mayer, Joshua Svaren, John J. Biol. Chem. 281:15129-37 11956230 Pubmed 2002 The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway Ward, Yvona Yap, Seow-Fong Ravichandran, V Matsumura, Fumio Ito, Masaaki Spinelli, Beth Kelly, Kathleen J. Cell Biol. 157:291-302 Reactome Database ID Release 78 9863230 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9863230 Reactome R-MMU-9031628 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9031628.1 NGF stimulation induces expression of a wide array of transcriptional targets. In rat PC12 cells, a common model for NGF signaling, stimulation with NGF causes cells to exit the cell cycle and undergo a differentiation program leading to neurite outgrowth. This program is driven by the expression of immediate early genes (IEGs), which frequently encode transcription factors regulating the activity of NGF-specific delayed response genes (reviewed in Sheng and Greenberg, 1990; Flavell and Grennberg, 2008; Santiago and Bashaw, 2014). 2181374 Pubmed 1990 Strong association between c-myb and oestrogen-receptor expression in human breast cancer Guérin, M Sheng, Z M Andrieu, N Riou, G Oncogene 5:131-5 18558867 Pubmed 2008 Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system Flavell, Steven W Greenberg, Michael E Annu. Rev. Neurosci. 31:563-90 Reactome Database ID Release 78 9861238 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861238 Reactome R-MMU-198725 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-198725.1 An important function of the kinase cascade triggered by neurotrophins is to induce the phosphorylation and activation of transcription factors in the nucleus to initiate new programs of gene expression. Transcription factors directly activated by neurotrophin signalling are responsible for induction of immediate-early genes, many of which are transcription factors. These in turn are involved in the induction of delayed-early genes. 8833451 Pubmed 1996 Intracellular signaling pathways activated by neurotrophic factors Segal, RA Greenberg, ME Annu Rev Neurosci 19:463-89 Reactome Database ID Release 78 9860800 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860800 Reactome R-MMU-187037 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-187037.1 Trk receptors signal from the plasma membrane and from intracellular membranes, particularly from early endosomes. Signalling from the plasma membrane is fast but transient; signalling from endosomes is slower but long lasting. Signalling from the plasma membrane is annotated here. TRK signalling leads to proliferation in some cell types and neuronal differentiation in others. Proliferation is the likely outcome of short term signalling, as observed following stimulation of EGFR (EGF receptor). Long term signalling via TRK receptors, instead, was clearly shown to be required for neuronal differentiation in response to neurotrophins. 10851172 Pubmed 2000 Neurotrophin signal transduction in the nervous system Kaplan, DR Miller, FD Curr Opin Neurobiol 10:381-91 10579918 Pubmed 1999 Neurotrophin signaling via Trks and p75 Friedman, WJ Greene, LA Exp Cell Res 253:131-42 Signaling by NTRK2 (TRKB) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Activated NTRK2 signals through PLCG1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Activated PCLG1 dissociates from NTRK2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> BDNF,NTF4:p-5Y-NTRK2:p-4Y-PLCG1 Reactome DB_ID: 9855981 Converted from EntitySet in Reactome BDNF,NTF4:p-5Y-NTRK2 Reactome DB_ID: 9855979 BDNF:p-5Y-NTRK2 homodimer Reactome DB_ID: 9855968 BDNF:p-5Y-NTRK2 Reactome DB_ID: 9855966 BDNF homodimer Reactome DB_ID: 9855964 Bdnf BDNF P21237 Reactome DB_ID: 9855962 UniProt:P21237 Bdnf Bdnf FUNCTION Important signaling molecule that activates signaling cascades downstream of NTRK2 (PubMed:27457814). During development, promotes the survival and differentiation of selected neuronal populations of the peripheral and central nervous systems. Participates in axonal growth, pathfinding and in the modulation of dendritic growth and morphology. Major regulator of synaptic transmission and plasticity at adult synapses in many regions of the CNS. The versatility of BDNF is emphasized by its contribution to a range of adaptive neuronal responses including long-term potentiation (LTP), long-term depression (LTD), certain forms of short-term synaptic plasticity, as well as homeostatic regulation of intrinsic neuronal excitability (PubMed:8139657, PubMed:15486301, PubMed:17023662, PubMed:27457814, PubMed:29909994).SUBUNIT Monomers and homodimers (PubMed:7957235). Binds to NTRK2/TRKB (By similarity). Can form heterodimers with other neurotrophin family members, such as NTF3 and NTF4 (in vitro), but the physiological relevance of this is not clear (By similarity). BDNF precursor form: interacts with the heterodimer formed by NGFR and SORCS2. Mature BDNF has much lower affinity for the heterodimer formed by NGFR and SORCS2 (PubMed:24908487).TISSUE SPECIFICITY Expressed in the dorsal root ganglion and the spinal cord (at protein level) (PubMed:28111162). Detected in brain, especially in brain cortex, hippocampus, midbrain and cerebellum (PubMed:2369898, PubMed:8139657).INDUCTION Expression oscillates in a circadian manner in the suprachiasmatic nucleus (SCN) of the brain (PubMed:23785138). Expressed at higher levels during the dark period and at lower levels during the light period (PubMed:23785138). Up-regulated after sciatic nerve injury (PubMed:28111162).PTM Contrary to mature BDNF, the propeptide is N-glycosylated and glycosulfated.PTM Mature BDNF is produced by proteolytic removal of the propeptide, catalyzed by a FURIN family member. In addition, the precursor form is proteolytically cleaved within the propeptide, but this is not an obligatory intermediate for the production of mature BDNF (By similarity). Can be converted into mature BDNF by plasmin (PLG) (PubMed:15486301).DISRUPTION PHENOTYPE Mutant mice are smaller than wild-type littermates, and most die during the second week after birth. They exhibit impaired motor coordination and balance, head bobbing and tilting, and spinning during perionds of hyperactivity. Mutant mice display a strongly reduced number of neurons in the dorsal root ganglion, trigeminal ganglion, mesencephalic trigeminal nucleus, vestibular ganglion and nodose ganglion. Cell death of vestibular ganglion neurons is strongly increased 14 days after birth. The number of facial motor neurons and sympathetic superior cervical ganglion neurons are not decreased. Mutant mice display defects in the innervation of the inner ear, but respond to auditory stimuli. Tne inner ear from mutant mice has fewer nerve fibers that enter the sacculus, utricle and ampulla of the semicircular ducts, and axons fail to contact their target cells and terminate in the connective tissue adjacent to the sensory epithelia of the sacculus.SIMILARITY Belongs to the NGF-beta family. UniProt P21237 129 EQUAL 247 EQUAL Reactome Database ID Release 78 9855962 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855962 Reactome R-MMU-167028 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167028.1 2 Reactome Database ID Release 78 9855964 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855964 Reactome R-MMU-9024931 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9024931.1 1 P15209 phospho-Ntrk2 p-5Y-NTRK2 Reactome DB_ID: 9855959 UniProt:P15209 Ntrk2 Ntrk2 Trkb FUNCTION Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. Isoform GP95-TRKB may also play a role in neutrophin-dependent calcium signaling in glial cells and mediate communication between neurons and glia.ACTIVITY REGULATION The formation of active receptors dimers able to fully transduce the ligand-mediated signal, may be negatively regulated by the formation of inactive heterodimers with the non-catalytic isoforms (By similarity). The neuronal activity and the influx of calcium positively regulate the kinase activity and the internalization of the receptor which are both important for active signaling. Regulated by NGFR that may control the internalization of the receptor. NGFR may also stimulate the activation by BDNF compared to NTF3 and NTF4. SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades.SUBUNIT Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Interacts (phosphorylated upon activation by BDNF) with SHC1; mediates SHC1 phosphorylation and activation. Interacts (phosphorylated upon activation by BDNF) with PLCG1 and/or PLCG2; mediates PLCG1 phosphorylation and activation. Interacts with SH2B1 and SH2B2. Interacts with NGFR; may regulate the ligand specificity of the receptor (By similarity). Interacts with SORCS2; this interaction is important for normal targeting to post-synaptic densities in response to high-frequency stimulation (PubMed:27457814). Interacts (phosphorylated upon ligand-binding) with SH2D1A; regulates NTRK2. Interacts with SQSTM1 and KIDINS220 (By similarity). Interacts (phosphorylated upon ligand-binding) with FRS2; activates the MAPK signaling pathway (By similarity). Interacts with APPL1 (PubMed:21849472). Interacts with MAPK8IP3/JIP3 and KLC1; interaction with KLC1 is mediated by MAPK8IP3/JIP3 (By similarity). Interacts with SORL1; this interaction facilitates NTRK2 trafficking between synaptic plasma membranes, postsynaptic densities and cell soma, hence positively regulates BDNF signaling (PubMed:23977241).TISSUE SPECIFICITY Expressed in the brain, in neurons (at protein level) (PubMed:23977241). Detected in hippocampus (at protein level) (PubMed:27457814). Widely expressed in the central and peripheral nervous system. The different forms are differentially expressed in various cell types. Isoform GP95-TRKB is specifically expressed in glial cells.INDUCTION Expression oscillates in a circadian manner in the liver.PTM Phosphorylated. Undergoes ligand-mediated autophosphorylation that is required for interaction with SHC1 and PLCG1 and other downstream effectors (PubMed:27457814). Some isoforms are not phosphorylated (By similarity).PTM Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination regulates the internalization of the receptor.DISRUPTION PHENOTYPE Mice lacking isoform GP145-TRKB, the catalytic isoform, do not display feeding activity and die at P1. This is associated neuronal deficiencies in the central and the peripheral nervous systems.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily. UniProt P15209 516 EQUAL 702 EQUAL 706 EQUAL 707 EQUAL 817 EQUAL 32 EQUAL 822 EQUAL Reactome Database ID Release 78 9855959 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855959 Reactome R-MMU-9026475 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9026475.1 1 Reactome Database ID Release 78 9855966 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855966 Reactome R-MMU-9026474 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9026474.1 1 1 Reactome Database ID Release 78 9855968 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855968 Reactome R-MMU-9026465 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9026465.1 NTF4:p-5Y-NTRK2 homodimer Reactome DB_ID: 9855977 NTF4:p-5Y-NTRK2 Reactome DB_ID: 9855975 1 NTF4 homodimer Reactome DB_ID: 9855973 Ntf4 NTF4 Q80VU4 Reactome DB_ID: 9855971 UniProt:Q80VU4 Ntf4 Ntf4 Ntf5 FUNCTION Could serve as a target-derived trophic factor for sensory and sympathetic neurons.SIMILARITY Belongs to the NGF-beta family. UniProt Q80VU4 81 EQUAL 210 EQUAL Reactome Database ID Release 78 9855971 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855971 Reactome R-MMU-167063 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167063.1 2 Reactome Database ID Release 78 9855973 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855973 Reactome R-MMU-9025082 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9025082.1 1 Reactome Database ID Release 78 9855975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855975 Reactome R-MMU-9026509 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9026509.1 1 1 Reactome Database ID Release 78 9855977 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855977 Reactome R-MMU-9026514 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9026514.1 Reactome Database ID Release 78 9855979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9855979 Reactome R-MMU-9026521 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9026521.1 1 Q62077 phospho-Plcg1 p-4Y-PLCG1 Reactome DB_ID: 9771305 UniProt:Q62077 Plcg1 Plcg1 Plcg-1 FUNCTION Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, EGFR, FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Plays a role in actin reorganization and cell migration (By similarity).ACTIVITY REGULATION Activated by phosphorylation on tyrosine residues.SUBUNIT Interacts (via SH2 domain) with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with RALGPS1. Interacts (via SH2 domains) with VIL1 (phosphorylated at C-terminus tyrosine phosphorylation sites). Interacts (via SH2 domain) with RET (By similarity). Interacts with AGAP2 via its SH3 domain. Interacts with LAT (phosphorylated) upon TCR activation. Interacts (via SH3 domain) with the Pro-rich domain of TNK1. Associates with BLNK, VAV1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB in activated T-cells; which inhibits phosphorylation. Interacts with SHB. Interacts (via SH3 domain) with the Arg/Gly-rich-flanked Pro-rich domains of KHDRBS1/SAM68. This interaction is selectively regulated by arginine methylation of KHDRBS1/SAM68. Interacts with INPP5D/SHIP1, THEMIS and CLNK. Interacts with FLT4 and KIT. Interacts with AXL (By similarity). Interacts with SYK; activates PLCG1 (By similarity). Interacts with FLT1 (tyrosine-phosphorylated). Interacts (via SH2 domain) with PDGFRA and PDGFRB (tyrosine phosphorylated). Interacts with PIP5K1C. Interacts with NTRK1 and NTRK2 (phosphorylated upon ligand-binding). Interacts with TESPA1 (By similarity). Interacts with GRB2, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1.DOMAIN The SH3 domain mediates interaction with RALGPS1 (By similarity). The SH3 domain also mediates interaction with CLNK.PTM Tyrosine phosphorylated in response to signaling via activated FLT3, KIT and PDGFRA (By similarity). Tyrosine phosphorylated by activated FGFR1, FGFR2, FGFR3 and FGFR4. Tyrosine phosphorylated by activated FLT1 and KDR. Tyrosine phosphorylated by activated PDGFRB. The receptor-mediated activation of PL