BioPAX pathway converted from "Interleukin-3, Interleukin-5 and GM-CSF signaling" in the Reactome database. Interleukin-3, Interleukin-5 and GM-CSF signaling 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 The receptor is activated 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 High affinity binding complexes of interleukin receptors using the Common beta chain Reactome DB_ID: 9852287 GM-CSF:GM-CSF receptor alpha subunit:Common beta chain:JAK2 Reactome DB_ID: 9852217 plasma membrane GENE ONTOLOGY GO:0005886 IL3RB:JAK2 Reactome DB_ID: 9852215 Csf2rb CSF2RB P26955 Reactome DB_ID: 9852213 UniProt:P26955 Csf2rb Mus musculus NCBI Taxonomy 10090 UniProt P26955 17 EQUAL 897 EQUAL Reactome Database ID Release 82 9852213 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852213 Reactome R-MMU-879960 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-879960.1 Reactome http://www.reactome.org 1 JAK2 Q62120 Reactome DB_ID: 9849246 cytosol GENE ONTOLOGY GO:0005829 UniProt:Q62120 Jak2 Jak2 FUNCTION Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.ACTIVITY REGULATION Regulated by autophosphorylation, can both activate or decrease activity (PubMed:8343951, PubMed:20304997, PubMed:21726629). Heme regulates its activity by enhancing the phosphorylation on Tyr-1007 and Tyr-1008 (By similarity).SUBUNIT Interacts with IL23R, SKB1 and STAM2 (By similarity). Interacts with EPOR (PubMed:8343951, PubMed:11779507). Interacts with LYN (PubMed:9573010). Interacts with SIRPA (PubMed:10842184). Interacts with SH2B1 (PubMed:17565041, PubMed:16824542). Interacts with TEC (PubMed:9473212). Interacts with IFNGR2 (via intracellular domain) (By similarity). Interacts with LEPR (Isoform B) (PubMed:11923481). Interacts with HSP90AB1; promotes functional activation in a heat shock-dependent manner. Interacts with STRA6 (By similarity). Interacts with ASB2; the interaction targets JAK2 for Notch-induced proteasomal degradation (By similarity).TISSUE SPECIFICITY Ubiquitously expressed throughout most tissues.DOMAIN Possesses 2 protein kinase domains. The second one probably contains the catalytic domain, while the presence of slight differences suggest a different role for protein kinase 1.PTM Autophosphorylated, leading to regulate its activity. Leptin promotes phosphorylation on tyrosine residues, including phosphorylation on Tyr-813 (PubMed:16824542, PubMed:17565041). Autophosphorylation on Tyr-119 in response to EPO down-regulates its kinase activity (PubMed:17024180). Autophosphorylation on Tyr-868, Tyr-966 and Tyr-972 in response to growth hormone (GH) are required for maximal kinase activity (PubMed:20304997). Also phosphorylated by TEC (PubMed:9473212). Phosphorylated on tyrosine residues in response to interferon gamma signaling (By similarity). Phosphorylated on tyrosine residues in response to a signaling cascade that is activated by increased cellular retinol (PubMed:21368206).PTM Undergoes Notch-induced ubiquitination and subsequent proteasomal degradation which is mediated by ASB1 or ASB2, the substrate-recognition components of probable ECS E3 ubiquitin-protein ligase complexes.DISRUPTION PHENOTYPE Embryos are anemic and die around day 12.5 post-coitum (dpc). Primitive erythrocytes are found, but definitive erythropoiesis is absent. Fetal liver myeloid progenitors, although present based on the expression of lineage specific markers, fail to respond to erythropoietin (Epo), thrombopoietin (Thpo), interleukin-3 (Il3), or granulocyte and macrophage colony-stimulating factor 1 (Csf1 and Csf2). Fetal liver BFU-E and CFU-E colonies are completely absent. However, multilineage hematopoietic stem cells (CD34(low), c-kit(pos)) can be found, and B-lymphopoiesis appears intact.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily. UniProt Q62120 1 EQUAL 1132 EQUAL Reactome Database ID Release 82 9849246 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9849246 Reactome R-MMU-210620 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-210620.1 1 Reactome Database ID Release 82 9852215 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852215 Reactome R-MMU-879945 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-879945.1 1 GM-CSF:GM-CSF receptor alpha subunit Reactome DB_ID: 9850304 Csf2 CSF2 P01587 Reactome DB_ID: 9850302 extracellular region GENE ONTOLOGY GO:0005576 UniProt:P01587 Csf2 UniProt P01587 18 EQUAL 144 EQUAL Reactome Database ID Release 82 9850302 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850302 Reactome R-MMU-517562 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-517562.1 1 Ghost homologue of CSF2RA Reactome DB_ID: 9850298 Reactome Database ID Release 82 9850298 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850298 Reactome R-MMU-913361 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-913361.1 1 Reactome Database ID Release 82 9850304 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850304 Reactome R-MMU-913362 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-913362.1 1 Reactome Database ID Release 82 9852217 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852217 Reactome R-MMU-913389 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-913389.1 IL5 homodimer:IL5RA:Common beta chain:JAK2 Reactome DB_ID: 9852221 1 IL5 homodimer:IL5RA Reactome DB_ID: 9850330 IL5 homodimer Reactome DB_ID: 9850328 Ghost homologue of IL5 Reactome DB_ID: 9850326 Reactome Database ID Release 82 9850326 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850326 Reactome R-MMU-447159 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-447159.1 2 Reactome Database ID Release 82 9850328 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850328 Reactome R-MMU-913383 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-913383.1 1 Il5ra IL5RA P21183 Reactome DB_ID: 9850324 UniProt:P21183 Il5ra UniProt P21183 21 EQUAL 420 EQUAL Reactome Database ID Release 82 9850324 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850324 Reactome R-MMU-450072 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-450072.1 1 Reactome Database ID Release 82 9850330 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850330 Reactome R-MMU-450056 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-450056.1 1 Reactome Database ID Release 82 9852221 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852221 Reactome R-MMU-913423 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-913423.1 Reactome Database ID Release 82 9852287 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852287 Reactome R-MMU-913364 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-913364.1 2 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2 Reactome DB_ID: 9852225 High affinity GM-CSF receptor complex dimer, inactive JAK2 Reactome DB_ID: 9852219 2 Reactome Database ID Release 82 9852219 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852219 Reactome R-MMU-913413 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-913413.1 High affinity IL-5 receptor complex dimer, inactive JAK2 Reactome DB_ID: 9852223 2 Reactome Database ID Release 82 9852223 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852223 Reactome R-MMU-913415 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-913415.1 Reactome Database ID Release 82 9852225 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852225 Reactome R-MMU-913399 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-913399.1 Reactome Database ID Release 82 9852289 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852289 Reactome R-MMU-879942 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-879942.1 Upon ligand binding to the alpha subunit, the alpha and Bc subunits asociate, forming a high affinity receptor. Subsequent signaling may require a disulfide-linked association between the alpha and beta chains (Stomski et al. 1996). While the formation of a 1:1:1 complex of interleukin:alpha subunit:common beta subunit represents a high-affinity binding complex, receptor activation involves the formation of higher order multimeric structures. The stoichiometry of endogenous active receptor complexes is not clear, but studies using dominant-negative, chimeric, and mutant receptors and modeling studies all suggest that a minimum of two Bc subunits are required for receptor activation and signaling (Guthridge et al. 1998, Hansen et al. 2008).<br><br> The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One such site is Y766, numbered according to the Uniprot canonical sequence. Note that in many publications this position is numbered as 750, referring to the mature sequence with signal peptide removed. These phosphorylations are mediated by receptor-associated kinases with JAK2 as the most likely candidate (Quelle et al. 1994, Guthridge et al. 1998). Specific phosphorylations appear to mediate association with different signaling components (Sato et al. 1993), e.g. substitution of F for Y766 prevents Shc phosphorylation (Inhorn et al. 1995) but not JAK2 phosphorylation. Modeling and structural data suggest that the active receptor is at least a dimer of ligand:alpha subunit:common beta subunit complexes (Bagley et al. 1997, Guthridge et al. 1998, Hansen et al. 2008). This fits a model of receptor activation whereby dimerization leads to Jak2 activation by transphosphorylation of the activation sites (Ihle et al. 1995, Guthridge et al. 1998, Hansen et al. 2008), leading to Bc activation by phosphorylation. The active receptors are represented here as dimers of ligand:alpha subunit:common beta subunit complexes. 1400495 Pubmed 1992 Tyrosine phosphorylation of receptor beta subunits and common substrates in response to interleukin-3 and granulocyte-macrophage colony-stimulating factor Duronio, V Clark-Lewis, I Federsppiel, B Wieler, JS Schrader, JW J Biol Chem 267:21856-63 7612228 Pubmed 1995 Signaling through the hematopoietic cytokine receptors Ihle, JN Witthuhn, BA Quelle, FW Yamamoto, K Silvennoinen, O Annu Rev Immunol 13:369-98 8649415 Pubmed 1996 Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding Stomski, FC Sun, Q Bagley, CJ Woodcock, J Goodall, G Andrews, RK Berndt, MC Lopez, Angel Mol Cell Biol 16:3035-46 9057626 Pubmed 1997 The structural and functional basis of cytokine receptor activation: lessons from the common beta subunit of the granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 receptors Bagley, CJ Woodcock, JM Stomski, FC Lopez, Angel Blood 89:1471-82 18692472 Pubmed 2008 The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation Hansen, G Hercus, TR McClure, BJ Stomski, FC Dottore, M Powell, J Ramshaw, H Woodcock, JM Xu, Y Guthridge, M McKinstry, WJ Lopez, Angel Parker, MW Cell 134:496-507 1396555 Pubmed 1992 Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation Sakamaki, K Miyajima, I Kitamura, T Miyajima, A EMBO J 11:3541-9 2681215 Pubmed 1989 Interleukin-3 stimulates the tyrosine phosphorylation of the 140-kilodalton interleukin-3 receptor Sorensen, P Mui, AL Krystal, G J Biol Chem 264:19253-8 7567993 Pubmed 1995 Identification of a viability domain in the granulocyte/macrophage colony-stimulating factor receptor beta-chain involving tyrosine-750 Inhorn, RC Carlesso, N Durstin, M Frank, DA Griffin, JD Proc Natl Acad Sci U S A 92:8665-9 8007942 Pubmed 1994 JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region Quelle, FW Sato, N Witthuhn, BA Inhorn, RC Eder, M Miyajima, A Griffin, JD Ihle, JN Mol Cell Biol 14:4335-41 9422786 Pubmed 1998 Identification of a Cys motif in the common beta chain of the interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 receptors essential for disulfide-linked receptor heterodimerization and activation of all three receptors Stomski, FC Woodcock, JM Zacharakis, B Bagley, CJ Sun, Q Lopez, Angel J Biol Chem 273:1192-9 9766809 Pubmed 1998 Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors Guthridge, MA Stomski, FC Thomas, D Woodcock, JM Bagley, CJ Berndt, MC Lopez, Angel Stem Cells 16:301-13 8647804 Pubmed 1996 Evidence for a physical association between the Shc-PTB domain and the beta c chain of the granulocyte-macrophage colony-stimulating factor receptor Pratt, JC Weiss, M Sieff, CA Shoelson, SE Burakoff, SJ Ravichandran, KS J Biol Chem 271:12137-40 8223433 Pubmed 1993 Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling Sato, N Sakamaki, K Terada, N Arai, K Miyajima, A EMBO J 12:4181-9 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT 2.7.10.2 JAK2 is phosphorylated, activated 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 82 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 additional information MI MI:0361 6 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 82 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 6 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2 Reactome DB_ID: 9852259 High affinity GM-CSF receptor complex dimer, activated JAK2 Reactome DB_ID: 9852240 GM-CSF:GM-CSF receptor alpha subunit:Common beta chain:p-JAK2 Reactome DB_ID: 9852231 IL3RB:p-Y1007-JAK2 Reactome DB_ID: 9852229 1 Q62120 phospho-p-Y1007-JAK2 Reactome DB_ID: 9822611 1007 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1 EQUAL 1132 EQUAL Reactome Database ID Release 82 9822611 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9822611 Reactome R-MMU-873799 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-873799.1 1 Reactome Database ID Release 82 9852229 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852229 Reactome R-MMU-893554 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-893554.1 1 1 Reactome Database ID Release 82 9852231 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852231 Reactome R-MMU-913443 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-913443.1 2 Reactome Database ID Release 82 9852240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852240 Reactome R-MMU-913379 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-913379.1 High affinity IL-5 receptor complex dimer, p-JAK2 Reactome DB_ID: 9852244 IL5 homodimer:IL5RA:Common beta chain:p-JAK2 Reactome DB_ID: 9852233 1 1 Reactome Database ID Release 82 9852233 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852233 Reactome R-MMU-913363 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-913363.1 2 Reactome Database ID Release 82 9852244 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852244 Reactome R-MMU-913457 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-913457.1 Reactome Database ID Release 82 9852259 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852259 Reactome R-MMU-913405 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-913405.1 ACTIVATION activeUnit: #Protein2 GENE ONTOLOGY GO:0004715 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 82 9852260 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852260 Reactome Database ID Release 82 9852262 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852262 Reactome R-MMU-879910 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-879910.1 JAK2 is tyrosine phosphorylated in response to IL-3 (Silvennoinen et al. 1993), GM-CSF (Quelle et al. 1994) and IL-5 (Cornelis et al. 1995) leading to kinase activity. Although structures of JAK kinase domains exist (e.g. Lucet et al. 2006) no complete structures of Janus kinases (JAKs) are available and the activation mechanism is poorly understood. Activation is believed to be a consequence of conformational changes, propagated from conformational changes in the common beta chain (Bc) following alpha-beta dimerization. This is believed to result in a trans-activation event whereby JAKs bound to activated, dimerized receptors phosphorylate and thereby activate each other (Quelle et al. 1994, Hou et al. 2002). This model is similar to IL2R activation of JAK1/3. In addition to the observed activation of JAK2 following stimulation with IL-3, IL-5 or GM-CSF, other supporting observations include: phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006) and autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the critical Y1007 phosphorylation is represented for this reaction.<br><br>Constitutive activation of JAK2 resulting from the V617F mutation is present in over 95% of Polycythemia Vera patients (Dusa et al. 2010). F595 is indispensible for constitutive activation by V617F, but not for JAK2 activation, suggesting that this is not part of the cytokine-induced mechansim of JAK2 activation. 15143188 Pubmed 2004 Tyrosine phosphorylation of Jak2 in the JH2 domain inhibits cytokine signaling Feener, EP Rosario, F Dunn, SL Stancheva, Z Myers MG, Jr Mol Cell Biol 24:4968-78 15143187 Pubmed 2004 Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity Argetsinger, LS Kouadio, JL Steen, H Stensballe, A Jensen, ON Carter-Su, C Mol Cell Biol 24:4955-67 8378315 Pubmed 1993 Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction Silvennoinen, O Witthuhn, BA Quelle, FW Cleveland, JL Yi, T Ihle, JN Proc Natl Acad Sci U S A 90:8429-33 7542592 Pubmed 1995 Characterization of critical residues in the cytoplasmic domain of the human interleukin-5 receptor alpha chain required for growth signal transduction Cornelis, S Fache, I Van der Heyden, J Guisez, Y Tavernier, J Devos, R Fiers, W Plaetinck, G Eur J Immunol 25:1857-64 16174768 Pubmed 2006 The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor Lucet, IS Fantino, E Styles, M Bamert, R Patel, O Broughton, SE Walter, M Burns, CJ Treutlein, H Wilks, AF Rossjohn, J Blood 107:176-83 20304997 Pubmed 2010 Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity Argetsinger, LS Stuckey, JA Robertson, SA Koleva, RI Cline, JM Marto, JA Myers MG, Jr Carter-Su, C Mol Endocrinol 24:1062-76 12479803 Pubmed 2002 The Jak/STAT pathway in model organisms: emerging roles in cell movement Hou, SX Zheng, Z Chen, X Perrimon, N Dev Cell 3:765-78 20585391 Pubmed 2010 JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors Dusa, A Mouton, C Pecquet, C Herman, M Constantinescu, SN PLoS One 5:e11157 9111318 Pubmed 1997 Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop Feng, J Witthuhn, BA Matsuda, T Kohlhuber, F Kerr, IM Ihle, JN Mol Cell Biol 17:2497-501 LEFT-TO-RIGHT STAT5 is recruited by JAK2 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 STAT5 STAT5A,STAT5B Reactome DB_ID: 9850269 Stat5a STAT5A P42230 Reactome DB_ID: 9843189 UniProt:P42230 Stat5a Stat5a Mgf Mpf FUNCTION Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Binds to the GAS element and activates PRL-induced transcription. Regulates the expression of milk proteins during lactation.SUBUNIT Forms a homodimer or a heterodimer with a related family member. Interacts with NCOA1 and SOCS7 (By similarity). Binds NR3C1. Interacts with ERBB4.TISSUE SPECIFICITY In the virgin, found in most tissues except brain and muscle. During lactation, abundantly found in mammary tissue, as well as in other secretory organs such as salivary gland and seminal vesicle.PTM ISGylated.PTM Tyrosine phosphorylated in response to KITLG/SCF, IL2, IL3, IL7, IL15, CSF2/GMCSF, GH1, PRL, EPO and THPO (PubMed:16837552). Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus (PubMed:21135090). Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Tyrosine phosphorylation is required for DNA-binding activity and dimerization (PubMed:7720707). Serine phosphorylation is also required for maximal transcriptional activity (By similarity). Tyrosine phosphorylated in response to signaling via activated FLT3; wild-type FLT3 results in much weaker phosphorylation than constitutively activated mutant FLT3 (PubMed:11090077, PubMed:21262971). Alternatively, can be phosphorylated by JAK2 at Tyr-694 (By similarity).SIMILARITY Belongs to the transcription factor STAT family. UniProt P42230 1 EQUAL 794 EQUAL Reactome Database ID Release 82 9843189 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9843189 Reactome R-MMU-380747 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-380747.1 Stat5b STAT5B P42232 Reactome DB_ID: 9843192 UniProt:P42232 Stat5b Stat5b FUNCTION Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Binds to the GAS element and activates PRL-induced transcription. Positively regulates hematopoietic/erythroid differentiation.SUBUNIT Upon activation, forms a homodimer or a heterodimer with a related family member. Binds NR3C1 (PubMed:9528750). Interacts with NCOA1 (By similarity). Interacts with SOCS7 (By similarity). Interacts (via SH2 domain) with INSR (PubMed:9428692). Interacts with CPEB3; this inhibits STAT5B-mediated transcriptional activation (PubMed:20639532).TISSUE SPECIFICITY In the virgin, found in most tissues. Particularly abundant in muscle tissue of virgin and lactating females, and of males.DEVELOPMENTAL STAGE Detected both in virgin mouse and after mammary gland involution. The level of STAT5A increases constantly during pregnancy, but decreases during lactation.PTM Tyrosine phosphorylated in response to signaling via activated KIT, resulting in translocation to the nucleus. Tyrosine phosphorylated in response to signaling via activated FLT3; wild-type FLT3 results in much weaker phosphorylation than constitutively activated mutant FLT3. Alternatively, can be phosphorylated by JAK2 (By similarity). Phosphorylation at Tyr-699 by PTK6 or HCK leads to an increase of its transcriptional activity (By similarity).SIMILARITY Belongs to the transcription factor STAT family. UniProt P42232 1 EQUAL 787 EQUAL Reactome Database ID Release 82 9843192 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9843192 Reactome R-MMU-380737 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-380737.1 Reactome Database ID Release 82 9850269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850269 Reactome R-MMU-452094 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-452094.1 3 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc. activated JAK2:STAT5 Reactome DB_ID: 9852248 High affinity GM-CSF receptor complex dimer, activated JAK2:STAT5 Reactome DB_ID: 9852242 1 1 Reactome Database ID Release 82 9852242 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852242 Reactome R-MMU-913386 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-913386.1 High affinity IL-5 receptor complex dimer, activated JAK2:STAT5 Reactome DB_ID: 9852246 1 1 Reactome Database ID Release 82 9852246 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852246 Reactome R-MMU-913407 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-913407.1 Reactome Database ID Release 82 9852248 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852248 Reactome R-MMU-913447 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-913447.1 Reactome Database ID Release 82 9852283 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852283 Reactome R-MMU-879930 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-879930.1 Activated JAK2 binds to unphosphorylated STAT5; cytokine treatment of cells leads to JAK2 activation and promotes binding of JAK2 to unphosphorylated STAT5.<br><br><br>STAT5 proteins are considered the main targets of IL-3, IL-5 and GM-CSF signaling (Mui et al. 1995a, Mui et al. 1995b, Ihle, 2001), but other members of this family including STAT3 and STAT1 (Chin et al. 1996) can be involved, the STAT family member activated appears to depend on the cell line used in the study, rather than the cytokine (Reddy et al. 2000). IL-5 and GM-CSF increase STAT3 and 5 signaling (Caldenhoven et al. 1995, Stout et al. 2004). <br><br><br>Unphosphorylated STATs are cytoplasmic; tyrosine phosphorylation facilitates dimerization and translocation to the nucleus where they act as transcription factors. STATs were originally described as ligand-induced transcription factors in interferon-treated cells, subsequently they were shown to be critical in many signal transduction pathways associated with cytokines and neurokines including several interleukins, the interferons, erythropoietin, prolactin, growth hormone, oncostatin M (OSM), and ciliary neurotrophic factor (Darnell 1997, Reddy et al. 2000). JAK-STAT signaling is widely accepted as a primary signaling route for receptors that share the common beta subunit (Bc). <br>The role of the receptor itself in STAT5 binding is somewhat controversial because while STAT proteins can be recruited to tyrosine phosphorylated receptors via their SH2 domains (Greenlund et al. 1995, Li et al. 1997) binding of STAT5 to Bc has not been formally demonstrated (Guthridge et al. 1998), though tyrosine-phosphorylated peptides of Bc have been demonstrated to associate with STAT5, and anti-Bc or phosphotyrosine antibodies inhibited GM-CSF induced STAT5 DNA binding activity (Sakurai et al. 2000). Binding of JAK2 to STAT5 can occur in vitro when no receptor is present (Flores-Morales et al. 1998). STAT5 activation was seen when all six conserved cytoplasmic tyrosines in Bc were mutated to P (Okuda et al. 1997), but a C-terminal deletion mutant of Bc while able to activate JAK2 was unable to activate STAT5 (Smith et al. 1997). These observations suggest that JAK2 activation is a critical step in STAT signaling from Bc-containing receptors, but other factors may be required. It is not clear whether Bc is directly involved or not in STAT5 activation, but the specificity for particular STAT members is believed to be determined by STAT docking sites present on the receptor molecules, not JAK kinase preference (Reddy et al. 2000). 9121453 Pubmed 1997 Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling Li, X Leung, S Kerr, IM Stark, GR Mol Cell Biol 17:2048-56 9630227 Pubmed 1998 Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses Teglund, S McKay, C Schuetz, E van Deursen, JM Stravopodis, D Wang, D Brown, M Bodner, S Grosveld, G Ihle, JN Cell 93:841-50 8614832 Pubmed 1996 Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1 Chin, YE Kitagawa, M Su, WC You, ZH Iwamoto, Y Fu, XY Science 272:719-22 9389692 Pubmed 1997 Signaling functions of the tyrosine residues in the betac chain of the granulocyte-macrophage colony-stimulating factor receptor Okuda, K Smith, L Griffin, JD Foster, R Blood 90:4759-66 9034328 Pubmed 1997 Cytoplasmic domains of the common beta-chain of the GM-CSF/IL-3/IL-5 receptors that are required for inducing differentiation or clonal suppression in myeloid leukaemic cell lines Smith, A Metcalf, D Nicola, NA EMBO J 16:451-64 7720707 Pubmed 1995 Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs Mui, AL Wakao, H O'Farrell, AM Harada, N Miyajima, A EMBO J 14:1166-75 10851052 Pubmed 2000 IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled Reddy, EP Korapati, A Chaturvedi, P Rane, S Oncogene 19:2532-47 7592760 Pubmed 1995 Activation of the STAT3/acute phase response factor transcription factor by interleukin-5 Caldenhoven, E van Dijk, T Raaijmakers, JA Lammers, JW Koenderman, L de Groot, RP J Biol Chem 270:25778-84 9685210 Pubmed 1998 In vitro interaction between STAT 5 and JAK 2; dependence upon phosphorylation status of STAT 5 and JAK 2 Flores-Morales, A Pircher, TJ Silvennoinen, O Gustafsson, JA Sanchez-Gomez, M Norstedt, G Haldosén, LA Wood, TJ Mol Cell Endocrinol 138:1-10 7796299 Pubmed 1995 Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process Greenlund, AC Morales, MO Viviano, BL Yan, H Krolewski, J Schreiber, RD Immunity 2:677-87 15528381 Pubmed 2004 IL-5 and granulocyte-macrophage colony-stimulating factor activate STAT3 and STAT5 and promote Pim-1 and cyclin D3 protein expression in human eosinophils Stout, BA Bates, ME Liu, LY Farrington, NN Bertics, PJ J Immunol 173:6409-17 7539031 Pubmed 1995 Interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5 transduce signals through two forms of STAT5 Mui, AL Wakao, H Harada, N O'Farrell, AM Miyajima, A J Leukoc Biol 57:799-803 11458499 Pubmed 2001 Pathways in cytokine regulation of hematopoiesis Ihle, J Ann N Y Acad Sci 938:129-30 11122381 Pubmed 2000 In vitro analysis of STAT5 activation by granulocyte-macrophage colony-stimulating factor Sakurai, Y Arai, K Watanabe, S Genes Cells 5:937-947 9287210 Pubmed 1997 STATs and gene regulation Darnell JE, Jr Science 277:1630-5 LEFT-TO-RIGHT 2.7.10.2 Activation of STAT5a/b by JAK2 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 6 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2:p-STAT5 Reactome DB_ID: 9852254 High affinity GM-CSF receptor complex dimer, activated JAK2:p-STAT5 Reactome DB_ID: 9852250 Converted from EntitySet in Reactome p-STAT5 p-STAT5A, p-STAT5B Reactome DB_ID: 9850277 P42230 phospho-Stat5a p-Y694-STAT5A Reactome DB_ID: 9850273 694 EQUAL 1 EQUAL 794 EQUAL Reactome Database ID Release 82 9850273 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850273 Reactome R-MMU-507936 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-507936.1 P42232 phospho-Stat5b p-Y699-STAT5B Reactome DB_ID: 9850275 699 EQUAL 1 EQUAL 787 EQUAL Reactome Database ID Release 82 9850275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850275 Reactome R-MMU-507939 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-507939.1 Reactome Database ID Release 82 9850277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850277 Reactome R-MMU-507929 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-507929.1 1 1 Reactome Database ID Release 82 9852250 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852250 Reactome R-MMU-913365 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-913365.1 High affinity IL-5 receptor complex dimer, activated JAK2:p-STAT5 Reactome DB_ID: 9852252 1 1 Reactome Database ID Release 82 9852252 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852252 Reactome R-MMU-913409 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-913409.1 Reactome Database ID Release 82 9852254 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852254 Reactome R-MMU-913465 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-913465.1 ACTIVATION GENE ONTOLOGY GO:0004713 Reactome Database ID Release 82 9852255 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852255 Reactome Database ID Release 82 9852257 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852257 Reactome R-MMU-879909 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-879909.1 JAK2 phosphorylates STAT5; phosphorylated STAT5 dimerizes and translocates to the nucleus (Darnell et al., 1994), binds DNA and activates target genes including c-fos, pim-1, oncostatin M, and Id-1 (Mui et al. 1996). STAT5 activation is believed to be the primary signaling mechanism for Bc (Ihle, 2001). 8197455 Pubmed 1994 Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins Darnell JE, Jr Kerr, IM Stark, GR Science 264:1415-21 8665850 Pubmed 1996 Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation Mui, AL Wakao, H Kinoshita, T Kitamura, T Miyajima, A EMBO J 15:2425-33 LEFT-TO-RIGHT p-STAT5 dissociates from the receptor complex 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> 3 Reactome Database ID Release 82 9853749 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853749 Reactome R-MMU-921155 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-921155.1 Deletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believe to occur following the release of phosphorylated monomers (e.g. Turkson & Jove 2000). 11426647 Pubmed 2000 STAT proteins: novel molecular targets for cancer drug discovery Turkson, J Jove, R Oncogene 19:6613-26 9030599 Pubmed 1997 A single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activation Behrmann, I Janzen, C Gerhartz, C Schmitz-Van de Leur, H Hermanns, H Heesel, B Graeve, L Horn, F Tavernier, J Heinrich, PC J Biol Chem 272:5269-74 LEFT-TO-RIGHT 2.7.10.2 Tyrosine kinases phosphorylate the 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> 12 12 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)-Bc Reactome DB_ID: 9852227 High affinity GM-CSF receptor complex dimer, inactive JAK2, p(Y593, 628)- Bc Reactome DB_ID: 9850316 GM-CSF:GM-CSF receptor alpha subunit:p(Y593, 628)-Bc:JAK2 Reactome DB_ID: 9850314 1 pY593,Y628-IL3RB:JAK2 Reactome DB_ID: 9850312 1 P26955 phospho-Csf2rb p-Y593,Y628-CSF2RB Reactome DB_ID: 9850310 593 EQUAL 628 EQUAL 17 EQUAL 897 EQUAL Reactome Database ID Release 82 9850310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850310 Reactome R-MMU-912312 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-912312.1 1 Reactome Database ID Release 82 9850312 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850312 Reactome R-MMU-912316 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-912316.1 1 Reactome Database ID Release 82 9850314 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850314 Reactome R-MMU-913355 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-913355.1 2 Reactome Database ID Release 82 9850316 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850316 Reactome R-MMU-913384 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-913384.1 High affinity IL-5 receptor complex dimer, inactive JAK2, p(Y593, 628)-Bc Reactome DB_ID: 9850334 IL5 homodimer:IL5RA:p(Y593, 628)-Bc:JAK2 Reactome DB_ID: 9850332 1 1 Reactome Database ID Release 82 9850332 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850332 Reactome R-MMU-913357 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-913357.1 2 Reactome Database ID Release 82 9850334 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850334 Reactome R-MMU-913359 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-913359.1 Reactome Database ID Release 82 9852227 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852227 Reactome R-MMU-913422 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-913422.1 ACTIVATION activeUnit: #Protein5 Converted from EntitySet in Reactome Tyrosine kinases that phosphorylate the Common beta chain Reactome DB_ID: 9852235 Reactome Database ID Release 82 9852235 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852235 Reactome R-MMU-904816 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-904816.1 Reactome Database ID Release 82 9852236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852236 Reactome Database ID Release 82 9852238 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852238 Reactome R-MMU-879907 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-879907.1 Phosphorylation of the receptor common beta chain (Bc) creates binding sites for proteins that trigger subsequent signaling cascades (Pawson & Scott, 1997). The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One site is Y766 (numbered as Y750 by Sakamaki et al. 1992 and many other publications). Phosphorylation of Bc in response to GM-CSF/IL3 is observed at low temperatures (4 degrees C) that prevent the phosphorylation of other proteins, suggesting that the kinase responsible is likely to be physically associated with the receptor complex prior to stimulation (Miyajima et al. 1993). JAK2 is activated in response to IL-3, IL-5 and GM-CSF but signaling via JAK/STAT is not dependent on Bc tyrosine phosphorylation (Okuda et al. 1997). Based on these observations and the role of JAK1/3 in IL-2 signaling, JAK2 is believed to be the most likely candidate responsible for the phosphorylation of Bc (Guthridge et al. 1998). To represent the possible phosphorylation of Bc by kinases other than JAK2, this reaction includes receptor complexes with both active and inactive JAK2. Phosphorylation is represented only where this is necesssary for subsequent signaling; phosphorylation at other positions is probable. 8400249 Pubmed 1993 Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5 Miyajima, A Mui, AL Ogorochi, T Sakamaki, K Blood 82:1960-74 9405336 Pubmed 1997 Signaling through scaffold, anchoring, and adaptor proteins Pawson, T Scott, JD Science 278:2075-80 LEFT-TO-RIGHT Recruitment of SHC1 is mediated by Y593 of the common beta chain 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> Shc1 SHC1 P98083 Reactome DB_ID: 9820615 UniProt:P98083-2 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 Isoform P98083-2 1 EQUAL 583 EQUAL Reactome Database ID Release 82 9820615 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9820615 Reactome R-MMU-74680 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-74680.1 3 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)-Bc:SHC1 Reactome DB_ID: 9852281 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:SHC1 Reactome DB_ID: 9852277 1 1 Reactome Database ID Release 82 9852277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852277 Reactome R-MMU-913433 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-913433.1 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:SHC1 Reactome DB_ID: 9852279 1 1 Reactome Database ID Release 82 9852279 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852279 Reactome R-MMU-913387 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-913387.1 Reactome Database ID Release 82 9852281 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852281 Reactome R-MMU-913458 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-913458.1 Reactome Database ID Release 82 9852285 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852285 Reactome R-MMU-879934 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-879934.1 Upon receptor activation, Shc is recruited to the receptor complex, where it becomes tyrosine phosphorylated. The recruitment of Shc is mediated by Y593 (Y577 in the mature peptide) of the common beta chain (Bc), which binds the PTB domain of Shc (Pratt et al. 1996). Phosphorylated Shc interacts with Grb2 within a Grb2:Gab2 complex, promoting tyrosine phosphorylation of Gab2. The p85 subunit of PI3Kinases associates with phosphorylated Gab, and this induces activation of the catalytic p110 PI3K subunit leading to activation of Akt kinase, thereby regulating cell survival and/or proliferation. 10982827 Pubmed 2000 New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway Gu, H Maeda, H Moon, JJ Lord, JD Yoakim, M Nelson, BH Neel, BG Mol Cell Biol 20:7109-20 Interleukin receptor SHC signaling 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 Phosphorylated SHC1 recruits GRB2:GAB2 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 Interleukin receptor complexes with activated SHC1 Reactome DB_ID: 9850340 IL2:IL2R trimer p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHC Reactome DB_ID: 9850286 P98083 phospho-Shc1 p-Y-SHC1 Reactome DB_ID: 9850284 1 EQUAL 583 EQUAL Reactome Database ID Release 82 9850284 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850284 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 1 IL2:IL2R trimer p-(Y338,392,510) beta subunit:p-JAK1:JAK3 Reactome DB_ID: 9850263 Ghost homologue of IL2 Reactome DB_ID: 9849650 Reactome Database ID Release 82 9849650 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9849650 Reactome R-MMU-447099 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-447099.1 1 P52332 phospho-p-Y-JAK1 Reactome DB_ID: 9850236 UniProt:P52332 Jak1 Jak1 FUNCTION Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor as well as interleukin (IL)-10 receptor. Directly phosphorylates STAT but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors.SUBUNIT Interacts with IL31RA. Interacts with IFNAR2. Interacts with IFNGR1. Interacts with JAKMIP1. Interacts with SHB. Interacts (via N-terminus) with IL2RB and IL10RA (via its cytoplasmic domain) (By similarity). Interacts with FER (PubMed:12738762).DOMAIN The FERM domain mediates interaction with JAKMIP1.DOMAIN The protein kinase 1 domain is also called the pseudokinase domain and has a regulatory role through the transactivation of other JAK kinases associated with signaling receptors.DOMAIN The protein kinase 2 domain is the catalytically active domain.PTM Ubiquitinated by RNF125; leading to its degradation by the proteasome.PTM Autophosphorylated. Phosphorylated on tyrosine residues in response to interferon gamma signaling. Dephosphorylation of Tyr-1034 and Tyr-1034 by PTPN2 negatively regulates cytokine-mediated signaling.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily. UniProt P52332 1 EQUAL 1154 EQUAL Reactome Database ID Release 82 9850236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850236 Reactome R-MMU-451921 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-451921.1 1 Il2ra IL2RA P01590 Reactome DB_ID: 9849648 UniProt:P01590 Il2ra UniProt P01590 22 EQUAL 272 EQUAL Reactome Database ID Release 82 9849648 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9849648 Reactome R-MMU-450046 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-450046.1 1 IL2RG:JAK3 Reactome DB_ID: 9849569 Il2rg Cytokine receptor common subunit gamma IL2RG_MOUSE Il2rg Reactome DB_ID: 539020 UniProt:P34902 Il2rg Il2rg FUNCTION Common subunit for the receptors for a variety of interleukins (PubMed:7718508). Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15 (By similarity).SUBUNIT The gamma subunit is common to the IL2, IL4, IL7, IL15, IL21 and probably also the IL13 receptors. Interacts with SHB upon interleukin stimulation (By similarity). Interacts with IL9 (PubMed:7718508).DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.DOMAIN The box 1 motif is required for JAK interaction and/or activation.SIMILARITY Belongs to the type I cytokine receptor family. Type 5 subfamily. UniProt P34902 23 EQUAL 369 EQUAL Reactome Database ID Release 82 539020 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=539020 Reactome R-MMU-539020 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-539020.1 1 JAK3 Q62137 Reactome DB_ID: 9849567 UniProt:Q62137 Jak3 Jak3 FUNCTION Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.SUBUNIT Interacts with STAM2 and MYO18A. Interacts with SHB (By similarity).TISSUE SPECIFICITY In contrast with the ubiquitous expression of the other JAKs, JAK3 is predominantly expressed in hematopoietic tissues.DOMAIN Possesses two phosphotransferase domains. The second one contains the catalytic domain, while the presence of a pseudokinase domain is required for suppression of basal activity of JAK3.PTM Autophosphorylated, leading to regulate its activity. IL2 promotes phosphorylation on tyrosine residues, including autophosphorylation on Tyr-781 (By similarity). Dephosphorylation of Tyr-976 and Tyr-977 by PTPN2 negatively regulates cytokine-mediated signaling (By similarity).DISRUPTION PHENOTYPE Mice show a severe block in B-cell development at the pre-B stage in the bone marrow. Additionally, they possesses small thymuses revealing a defect in T-cell development. The distribution of developmental subsets is relatively normal, suggesting a block in the expansion of early T-cell progenitors. Peripheral T-cells are present at normal or increased numbers but are functionally incompetent.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily. UniProt Q62137 1 EQUAL 1124 EQUAL Reactome Database ID Release 82 9849567 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9849567 Reactome R-MMU-451893 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-451893.1 1 Reactome Database ID Release 82 9849569 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9849569 Reactome R-MMU-451911 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-451911.1 1 P16297 phospho-Il2rb p-Y364,Y418,Y536-IL2RB Reactome DB_ID: 9850261 UniProt:P16297 Il2rb Il2rb FUNCTION Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15 (By similarity).SUBUNIT Non-covalent dimer of an alpha and a beta subunit. IL2R exists in 3 different forms: a high affinity dimer, an intermediate affinity monomer (beta subunit), and a low affinity monomer (alpha subunit). The high and intermediate affinity forms also associate with a gamma subunit. Interacts with SHB upon interleukin stimulation (By similarity).DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.DOMAIN The box 1 motif is required for JAK interaction and/or activation.SIMILARITY Belongs to the type I cytokine receptor family. Type 4 subfamily. UniProt P16297 364 EQUAL 418 EQUAL 536 EQUAL 27 EQUAL 551 EQUAL Reactome Database ID Release 82 9850261 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850261 Reactome R-MMU-452093 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-452093.1 1 Reactome Database ID Release 82 9850263 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850263 Reactome R-MMU-452119 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-452119.1 1 Reactome Database ID Release 82 9850286 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850286 Reactome R-MMU-453099 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-453099.1 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 Reactome DB_ID: 9850338 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1 Reactome DB_ID: 9850320 1 P98083 phospho-Shc1 p-Y349,Y350,Y427-SHC1 Reactome DB_ID: 9850318 427 EQUAL 349 EQUAL 350 EQUAL 1 EQUAL 583 EQUAL Reactome Database ID Release 82 9850318 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850318 Reactome R-MMU-912321 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-912321.1 1 Reactome Database ID Release 82 9850320 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850320 Reactome R-MMU-913428 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-913428.1 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1 Reactome DB_ID: 9850336 1 1 Reactome Database ID Release 82 9850336 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850336 Reactome R-MMU-913366 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-913366.1 Reactome Database ID Release 82 9850338 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850338 Reactome R-MMU-913439 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-913439.1 Reactome Database ID Release 82 9850340 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850340 Reactome R-MMU-912534 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-912534.1 GRB2:GAB2 Reactome DB_ID: 9850342 Gab2 GAB2 Q9Z1S8 Reactome DB_ID: 9837172 UniProt:Q9Z1S8 Gab2 Gab2 FUNCTION Adapter protein which acts downstream of several membrane receptors including cytokine, antigen, hormone, cell matrix and growth factor receptors to regulate multiple signaling pathways. Regulates osteoclast differentiation mediating the TNFRSF11A/RANK signaling. In allergic response, it plays a role in mast cells activation and degranulation through PI-3-kinase regulation. Also involved in the regulation of cell proliferation and hematopoiesis.SUBUNIT Interacts with HCK (By similarity). Interacts with SHC1; may mediate interaction with receptors. Interacts with SYK. Interacts with PI-3 kinase. Interacts with GRB2 (via SH3 2 domain). Interacts (phosphorylated) with PTPN11. Interacts with TNFRSF11A (via cytoplasmic domain). Interacts (phosphorylated) with 14-3-3 family proteins SFN, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ; prevents interaction with GRB2 and attenuates GAB2 signaling.TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN The SH3-binding motifs mediate interaction with SHC1 and GRB2.DOMAIN The PH domain mediates phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate binding.PTM Phosphorylated upon EGF stimulation. Phosphorylated on tyrosine residues by HCK upon IL6 signaling (By similarity). Phosphorylated on tyrosine residue(s) by the thrombopoietin receptor (TPOR), stem cell factor receptor (SCFR), and T-cell and B-cell antigen receptors, gp130, IL-2R and IL-3R. Phosphorylated upon stimulation of TNFRSF11A/RANK by TNFSF11/RANKL.PTM Dephosphorylated by PTPN11.DISRUPTION PHENOTYPE Mice are viable and healthy for up to 15 months. However, they have reduced number of mast cells and develop osteopetrosis.SIMILARITY Belongs to the GAB family. UniProt Q9Z1S8 1 EQUAL 676 EQUAL Reactome Database ID Release 82 9837172 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9837172 Reactome R-MMU-508239 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-508239.1 1 Grb2-1 Growth factor receptor-bound protein 2 GRB2_MOUSE Reactome DB_ID: 9029108 UniProt:Q60631-1 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 Isoform Q60631-1 1 EQUAL 217 EQUAL Reactome Database ID Release 82 9029108 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9029108 Reactome R-MMU-9029108 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-9029108.1 1 Reactome Database ID Release 82 9850342 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850342 Reactome R-MMU-912522 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-912522.1 4 Converted from EntitySet in Reactome Interleukin receptor compexes with activated Shc:GRB2:GAB2 Reactome DB_ID: 9850352 IL2:IL2R trimer p(Y338,392,510) beta subunit:p-SHC:GRB2:GAB2 Reactome DB_ID: 9850344 1 1 Reactome Database ID Release 82 9850344 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850344 Reactome R-MMU-508246 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-508246.1 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:GAB2 Reactome DB_ID: 9850350 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:GAB2 Reactome DB_ID: 9850346 1 1 Reactome Database ID Release 82 9850346 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850346 Reactome R-MMU-914021 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-914021.1 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:GAB2 Reactome DB_ID: 9850348 1 1 Reactome Database ID Release 82 9850348 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850348 Reactome R-MMU-914047 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-914047.1 Reactome Database ID Release 82 9850350 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850350 Reactome R-MMU-914052 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-914052.1 Reactome Database ID Release 82 9850352 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850352 Reactome R-MMU-912537 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-912537.1 Reactome Database ID Release 82 9850354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850354 Reactome R-MMU-453104 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-453104.1 Phosphorylated Shc recruits Grb2 and Gab2, probably by binding to Grb2 in the Grb2:Gab2 complex. Gab2 associates with Grb2, Shc, Shp2 and the p85 subunit of PI3K (Gu et al. 1998). The association of Grb2 with Gab2 has been suggested to be constitutive (Gu et al. 2000, Kong et al. 2003, Harkiolaki et al. 2009), so Gab2 may be recruited to Shc1 with Grb2. Alternatively, Gab2 has been suggested to associate constitutively with Shc (Kong et al 2003). In either case, the result is a complex of Shc:Grb2:Gab2. Gab2 binding to p85 (Gu et al. 1998) links Shc1 to PI3K activity and subsequent activation of kinases such as Akt (Gu et al. 2000). 9885561 Pubmed 1998 Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation Gu, H Pratt, JC Burakoff, SJ Neel, BG Mol Cell 2:729-40 12464621 Pubmed 2003 Epidermal growth factor-induced DNA synthesis. Key role for Src phosphorylation of the docking protein Gab2 Kong, M Mounier, C Dumas, V Posner, BI J Biol Chem 278:5837-44 19523899 Pubmed 2009 Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2 Harkiolaki, M Tsirka, T Lewitzky, M Simister, PC Joshi, D Bird, LE Jones, EY O'Reilly, N Feller, SM Structure 17:809-22 8084588 Pubmed 1994 Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins Salcini, AE McGlade, J Pelicci, G Nicoletti, I Pawson, T Pelicci, PG Oncogene 9:2827-36 LEFT-TO-RIGHT SHC1 mediates cytokine-induced phosphorylation of GAB2 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 Converted from EntitySet in Reactome Interleukin receptor complexes with activated Shc:GRB2:p-GAB2 Reactome DB_ID: 9851219 IL2:IL2R trimer p(Y338,392,510) beta subunit:p-SHC:GRB2:p(Y)-GAB2 Reactome DB_ID: 9851211 GRB2:p-Y-GAB2 Reactome DB_ID: 9851209 Q9Z1S8 phospho-Gab2 p-Y-GAB2 Reactome DB_ID: 9822508 1 EQUAL 676 EQUAL Reactome Database ID Release 82 9822508 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9822508 Reactome R-MMU-912529 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-912529.1 1 1 Reactome Database ID Release 82 9851209 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851209 Reactome R-MMU-912528 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-912528.1 1 1 Reactome Database ID Release 82 9851211 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851211 Reactome R-MMU-912523 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-912523.1 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2 Reactome DB_ID: 9851217 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2 Reactome DB_ID: 9851213 1 1 Reactome Database ID Release 82 9851213 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851213 Reactome R-MMU-926770 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-926770.1 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2 Reactome DB_ID: 9851215 1 1 Reactome Database ID Release 82 9851215 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851215 Reactome R-MMU-926769 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-926769.1 Reactome Database ID Release 82 9851217 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851217 Reactome R-MMU-926768 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-926768.1 Reactome Database ID Release 82 9851219 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851219 Reactome R-MMU-912533 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-912533.1 Reactome Database ID Release 82 9852667 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852667 Reactome R-MMU-912527 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-912527.1 Binding of Gab2 to tyrosine phosphorylated Shc promotes the phosphorylation of Gab2 by an unknown kinase. Gab2 becomes tyrosine phosphorylated in response to IL-2 (Brockdorff et al. 2001) and IL-3 (Gu et al. 1998). Chimeric receptors were used to demonstrate that Shc is sufficient for Gab2 tyrosine phosphorylation. In response to IL-3, Grb2 was also required, reflecting that Gab2 is recruited to the activated cytokine receptor complex as a complex of Gab2:Grb2 (Gu et al. 2000). 11340297 Pubmed 2001 Gab2 is phosphorylated on tyrosine upon interleukin-2/interleukin-15 stimulation in mycosis-fungoides-derived tumor T cells and associates inducibly with SHP-2 and Stat5a Brockdorff, JL Gu, H Mustelin, T Kaltoft, K Geisler, C Röpke, C Ødum, N Exp Clin Immunogenet 18:86-95 LEFT-TO-RIGHT Gab2 binds the p85 subunit of Class 1A PI3 kinases 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 p85-containing Class 1A PI3Ks Reactome DB_ID: 9851207 PI3K alpha Reactome DB_ID: 9823932 Converted from EntitySet in Reactome PI3K-regulatory subunits Reactome DB_ID: 9823930 Pik3r1 PIK3R1 P26450 Reactome DB_ID: 9820595 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). Interacts with TYK2 (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 82 9820595 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9820595 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: 9820598 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 82 9820598 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9820598 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 Pik3r3 PIK3R3 Q64143 Reactome DB_ID: 9823928 UniProt:Q64143 Pik3r3 Pik3r3 FUNCTION Binds to activated (phosphorylated) protein-tyrosine kinases through its SH2 domain and regulates their kinase activity. During insulin stimulation, it also binds to IRS-1.SUBUNIT Heterodimer of a regulatory subunit PIK3R3 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts with AXL (By similarity).TISSUE SPECIFICITY Highest levels in brain and testis. Lower levels in adipose tissue, kidney, heart, lung and skeletal muscle. Barely detectable in liver and spleen.SIMILARITY Belongs to the PI3K p85 subunit family. UniProt Q64143 1 EQUAL 461 EQUAL Reactome Database ID Release 82 9823928 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823928 Reactome R-MMU-205223 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-205223.1 Reactome Database ID Release 82 9823930 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823930 Reactome R-MMU-391342 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-391342.1 1 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 82 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 1 Reactome Database ID Release 82 9823932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9823932 Reactome R-MMU-198379 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-198379.1 PI3K beta Reactome DB_ID: 9848187 1 Pik3cb PIK3CB Q8BTI9 Reactome DB_ID: 9820604 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. Has also a protein kinase activity showing autophosphorylation.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.PTM Autophosphorylation at Ser-1064 negatively regulates the phosphatidylinositol-4,5-bisphosphate 3-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 82 9820604 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9820604 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 1 Reactome Database ID Release 82 9848187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9848187 Reactome R-MMU-437110 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-437110.1 PI3K delta Reactome DB_ID: 9851205 1 Pik3cd PIK3CD O35904 Reactome DB_ID: 9851203 UniProt:O35904 Pik3cd Pik3cd 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) (PubMed:9235916). 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. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Plays a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Plays important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function.ACTIVITY REGULATION Activated by growth factors and cytokine receptors through a tyrosine-kinase-dependent mechanism. Activated by RAS. IC87114 inhibits lipid kinase activity and is selective in cells at doses up to 5-10 uM. Among other effects, IC87114 reduces allergic responses, prevents the recruitment of antigen-specific T cells into target tissue, and affects natural killer cell chemotaxis.PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CD and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with ERAS and HRAS.TISSUE SPECIFICITY Abundantly expressed in adult mouse spleen as well as in testis (PubMed:9235916). Isoform 1 is expressed in spleen and lung (at protein level). Isoform 1 is expressed predominantly in leukocytes.PTM Autophosphorylation on Ser-1038 results in the almost complete inactivation of the lipid kinase activity.DISRUPTION PHENOTYPE Null mutants are viable and fertile but display defective adaptive and innate immune responses due to signaling defects in multiple cell types including B-, T- and mast and natural killer cells.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt O35904 1 EQUAL 1044 EQUAL Reactome Database ID Release 82 9851203 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851203 Reactome R-MMU-392274 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-392274.1 1 Reactome Database ID Release 82 9851205 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851205 Reactome R-MMU-508241 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-508241.1 Reactome Database ID Release 82 9851207 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851207 Reactome R-MMU-508248 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-508248.1 4 Converted from EntitySet in Reactome Interleukin receptor complexes with activated Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Ks Reactome DB_ID: 9851237 IL2:IL2R trimer p(Y338) beta subunit:p-SHC:GRB2:GAB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 9851221 1 1 Reactome Database ID Release 82 9851221 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851221 Reactome R-MMU-508238 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-508238.1 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 9851235 IL3:IL3R active complex, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 9851229 IL3:IL3R active complex, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2 Reactome DB_ID: 9851227 1 IL3:IL3R active complex, phosphorylated Bc:p(Y427,349,350)-SHC1 Reactome DB_ID: 9851225 1 Ghost homologue of IL3:IL3R active complex, phosphorylated Bc Reactome DB_ID: 9851223 Reactome Database ID Release 82 9851223 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851223 Reactome R-MMU-912320 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-912320.1 1 Reactome Database ID Release 82 9851225 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851225 Reactome R-MMU-912313 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-912313.1 1 Reactome Database ID Release 82 9851227 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851227 Reactome R-MMU-912540 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-912540.1 1 1 Reactome Database ID Release 82 9851229 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851229 Reactome R-MMU-912532 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-912532.1 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 9851231 1 1 Reactome Database ID Release 82 9851231 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851231 Reactome R-MMU-926773 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-926773.1 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 9851233 1 1 Reactome Database ID Release 82 9851233 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851233 Reactome R-MMU-926774 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-926774.1 Reactome Database ID Release 82 9851235 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851235 Reactome R-MMU-926776 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-926776.1 Reactome Database ID Release 82 9851237 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851237 Reactome R-MMU-912535 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-912535.1 Reactome Database ID Release 82 9851239 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851239 Reactome R-MMU-508247 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-508247.1 Shc promotes Gab2 tyrosine phosphorylation via Grb2 (Gu et al. 2000). This promotes binding of Gab2 to p85alpha, a component of Class 1A PI3Ks (Gu et al. 1998). JAK1 may also be involved in PI3K recruitment (Migone et al. 1998). Binding of p85 activates PI3K kinase activity, with consequent effects on many processes including Akt activation. This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors, the other is mediated by Serine-585 phosphorylation of the common beta chain. 9774657 Pubmed 1998 Functional cooperation of the interleukin-2 receptor beta chain and Jak1 in phosphatidylinositol 3-kinase recruitment and phosphorylation Migone, TS Rodig, S Cacalano, NA Berg, M Schreiber, RD Leonard, WJ Mol Cell Biol 18:6416-22 10455108 Pubmed 1999 Engagement of Gab1 and Gab2 in erythropoietin signaling Wickrema, A Uddin, S Sharma, A Chen, F Alsayed, Y Ahmad, S Sawyer, ST Krystal, G Yi, T Nishada, K Hibi, M Hirano, T Platanias, LC J Biol Chem 274:24469-74 LEFT-TO-RIGHT Phosphorylated SHC recruits GRB2:SOS1 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> GRB2-1:SOS1 Reactome DB_ID: 9820588 Sos1 SOS1 Q62245 Reactome DB_ID: 9820586 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 82 9820586 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9820586 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 1 Reactome Database ID Release 82 9820588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9820588 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 4 Interleukin receptor complexes with activated SHC1:GRB2:SOS1 Reactome DB_ID: 9850356 4 1 Reactome Database ID Release 82 9850356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850356 Reactome R-MMU-921157 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-921157.1 Reactome Database ID Release 82 9850358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850358 Reactome R-MMU-453111 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-453111.1 Shc is tyrosine phosphorylated by an unidentified kinase, creating a docking site for the SH2 domain of Grb2 (Zhu et al. 1994). Grb2 is an adaptor protein believed to be constitutively associated with the guanine nucleotide exchange protein Sos1 (often abbreviated to Sos). Recruitment of the Grb2:Sos1 complex leads to activation of the Ras pathway (Ravichandran & Burakoff 1994) and consequently activation of the MAPK pathway. 8119884 Pubmed 1994 Interleukin-2-induced tyrosine phosphorylation of Shc proteins correlates with factor-dependent T cell proliferation Zhu, X Suen, KL Barbacid, M Bolen, JB Fargnoli, J J Biol Chem 269:5518-22 1465135 Pubmed 1992 Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases Rozakis-Adcock, M McGlade, J Mbamalu, G Pelicci, G Daly, R Li, W Batzer, A Thomas, S Brugge, J Pelicci, PG Nature 360:689-92 8294403 Pubmed 1994 The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation Ravichandran, KS Burakoff, SJ J Biol Chem 269:1599-602 LEFT-TO-RIGHT Phosphorylated SHC1 recruits SHIP 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 SHIP1,2 Reactome DB_ID: 9852788 Inpp5d INPP5D Q9ES52 Reactome DB_ID: 9835682 UniProt:Q9ES52 Inpp5d UniProt Q9ES52 1 EQUAL 1189 EQUAL Reactome Database ID Release 82 9835682 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9835682 Reactome R-MMU-197940 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-197940.1 Inppl1 INPPL1 Q6P549 Reactome DB_ID: 9852786 UniProt:Q6P549 Inppl1 UniProt Q6P549 1 EQUAL 1258 EQUAL Reactome Database ID Release 82 9852786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852786 Reactome R-MMU-913354 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-913354.1 Reactome Database ID Release 82 9852788 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852788 Reactome R-MMU-913467 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-913467.1 4 Interleukin receptor complexes with activated SHC1:SHIP1,2 Reactome DB_ID: 9852790 1 4 Reactome Database ID Release 82 9852790 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852790 Reactome R-MMU-913393 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-913393.1 Reactome Database ID Release 82 9852792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852792 Reactome R-MMU-913374 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-913374.1 SHIP dephosphorylates PIP3 and may limit the magnitude or duration of signaling events that are dependent upon PIP3-mediated membrane recruitment of plextrin homology (PH) domain signalling proteins such as PI3K and Akt (Aman et al. 1998). The PTB domain of SHC1 binds to phosphorylated tyrosine residues on SHIP. Mutations that inactivate the PTB domain prevent this binding and substitution of F for Y917 and Y1020 on SHIP prevents creation of the phosphotyrosine motifs that are recognized by the SHC1 PTB domain, blocking the interaction (Lamkin et al. 1997). A functional SHIP SH2 domain is also reported as a requirement for association of SHIP with Shc (Liu et al. 1997). GRB2 stabilizes the SHC1/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on SHC1, forming a ternary complex of SHC1:GRB2:SHIP described as inducible by IL-3, IL-5 or GM-CSF by many authors (Jucker et al. 1997, Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999). 10194451 Pubmed 1999 A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells Wisniewski, Douglas Strife, A Swendeman, S Erdjument-Bromage, H Geromanos, S Kavanaugh, WM Tempst, P Clarkson, B Blood 93:2707-20 9108392 Pubmed 1997 Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl Odai, H Sasaki, K Iwamatsu, A Nakamoto, T Ueno, H Yamagata, T Mitani, K Yazaki, Y Hirai, H Blood 89:2745-56 9083021 Pubmed 1997 The Src homology 2 (SH2) domain of SH2-containing inositol phosphatase (SHIP) is essential for tyrosine phosphorylation of SHIP, its association with Shc, and its induction of apoptosis Liu, L Damen, JE Hughes, MR Babic, I Jirik, FR Krystal, G J Biol Chem 272:8983-8 9058724 Pubmed 1997 A tyrosine-phosphorylated protein of 140 kD is constitutively associated with the phosphotyrosine binding domain of Shc and the SH3 domains of Grb2 in acute myeloid leukemia cells Jücker, M Schiffer, CA Feldman, RA Blood 89:2024-35 10570274 Pubmed 1999 Tyrosine phosphorylation of shc in response to B cell antigen receptor engagement depends on the SHIP inositol phosphatase Ingham, RJ Okada, H Dang-Lawson, M Dinglasan, J van der Geer, P Kurosaki, T Gold, MR J Immunol 163:5891-5 10207047 Pubmed 1999 The src homology domain 2-containing inositol phosphatase SHIP forms a ternary complex with Shc and Grb2 in antigen receptor-stimulated B lymphocytes Harmer, SL DeFranco, AL J Biol Chem 274:12183-91 9852043 Pubmed 1998 The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells Aman, MJ Lamkin, TD Okada, H Kurosaki, T Ravichandran, KS J Biol Chem 273:33922-8 9099679 Pubmed 1997 Shc interaction with Src homology 2 domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP Lamkin, TD Walk, SF Liu, L Damen, JE Krystal, G Ravichandran, KS J Biol Chem 272:10396-401 7898932 Pubmed 1995 Overexpression of Shc proteins potentiates the proliferative response to the granulocyte-macrophage colony-stimulating factor and recruitment of Grb2/SoS and Grb2/p140 complexes to the beta receptor subunit Lanfrancone, L Pelicci, G Brizzi, MF Aronica, MG Casciari, C Giuli, S Pegoraro, L Pawson, T Pelicci, PG Arouica, MG Oncogene 10:907-17 LEFT-TO-RIGHT The SHC1:SHIP1 complex is stabilized by GRB2 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 Interleukin receptor complexes with activated SHC1:SHIP1 Reactome DB_ID: 9852794 1 PTPN6 P29351 Reactome DB_ID: 9837225 UniProt:P29351 Ptpn6 Ptpn6 Hcp Hcph Ptp1C FUNCTION Modulates signaling by tyrosine phosphorylated cell surface receptors such as KIT and the EGF receptor/EGFR. Enhances the inhibition of mast cell activation mediated by the Lilrb4a receptor (PubMed:10026201). The SH2 regions may interact with other cellular components to modulate its own phosphatase activity against interacting substrates. Together with MTUS1, induces UBE2V2 expression upon angiotensin II stimulation. Plays a key role in hematopoiesis.SUBUNIT Monomer. Interacts with MTUS1 (By similarity). Interacts with MILR1 (tyrosine-phosphorylated) (PubMed:20526344). Interacts with KIT (PubMed:9528781). Interacts with SIRPA/PTPNS1 (PubMed:9712903). Interacts with FCRL2 and FCRL4 (By similarity). Interacts with CD84 (By similarity). Interacts with CD300LF (PubMed:14662855). Interacts with CDK2 (By similarity). Interacts with KIR2DL1; the interaction is enhanced by ARRB2 (By similarity). Interacts (via SH2 1 domain) with ROS1; the interaction is direct and promotes ROS1 dephosphorylation (By similarity). Interacts with EGFR; inhibits EGFR-dependent activation of MAPK/ERK (By similarity). Interacts with LYN (By similarity). Interacts with the tyrosine phosphorylated form of PDPK1 (By similarity). Interacts with CEACAM1 (via cytoplasmic domain); this interaction depends on the monomer/dimer equilibrium and is phosphorylation-dependent (PubMed:19948503, PubMed:9867848). Interacts with MPIG6B (via ITIM motif) (PubMed:23112346). Interacts with KLRI1 and KLRI2 (By similarity). Interacts with moesin/MSN. Interacts with Lilrb4a (when tyrosine phosphorylated); the interaction enhances Lilrb4a-mediated inhibition of mast cell activation (PubMed:10026201, PubMed:9973385). Interacts with CLEC12B (via ITIM motif).TISSUE SPECIFICITY Expressed predominantly in hematopoietic cells.DOMAIN The N-terminal SH2 domain functions as an auto-inhibitory domain, blocking the catalytic domain in the ligand-free close conformation.PTM Phosphorylated on tyrosine residues. Phosphorylation at Tyr-564 enhances phosphatase activity (By similarity). Binding of KITLG/SCF to KIT increases tyrosine phosphorylation.DISEASE Defects in Ptpn6 are the cause of the motheaten (me) or viable motheaten (mev) phenotypes. Mice homozygous for the recessive allelic mutations develop severe defects in hematopoiesis.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily. UniProt P29351 1 EQUAL 595 EQUAL Reactome Database ID Release 82 9837225 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9837225 Reactome R-MMU-197938 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-197938.1 4 Reactome Database ID Release 82 9852794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852794 Reactome R-MMU-913378 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-913378.1 Interleukin receptor complexes with activated SHC1:SHIP:GRB2 Reactome DB_ID: 9852796 4 1 Reactome Database ID Release 82 9852796 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852796 Reactome R-MMU-913411 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-913411.1 Reactome Database ID Release 82 9852798 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852798 Reactome R-MMU-913424 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-913424.1 Grb2 stabilizes the Shc/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on Shc. This forms a ternary complex of SHC1:GRB2:SHIP described as an outcome of IL-3, IL-5 or GM-CSF stimulation (Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999). Reactome Database ID Release 82 9927154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9927154 Reactome R-MMU-912526 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-912526.1 Phosphorylation of Shc at three tyrosine residues, 239, 240 (Gotoh et al. 1996) and 317 (Salcini et al. 1994) involves unidentified tyrosine kinases presumed to be part of the activated receptor complex. These phosphorylated tyrosines subsequently bind SH2 signaling proteins such as Grb2, Gab2 and SHIP that are involved in the regulation of different signaling pathways. Grb2 can associate with the guanosine diphosphate-guanosine triphosphate exchange factor Sos1, leading to Ras activation and regulation of cell proliferation. Downstream signals are mediated via the Raf-MEK-Erk pathway.Grb2 can also associate through Gab2 with PI3K and with SHIP.<br><br>Figure reproduced from Gu, H. et al. 2000. Mol. Cell. Biol. 20(19):7109-7120<br>Copyright American Society for Microbiology. All Rights Reserved. 8947042 Pubmed 1996 A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL-3 Gotoh, N Tojo, A Shibuya, M EMBO J 15:6197-204 Regulation of signaling by CBL 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 CBL, GRB2, FYN and PI3K p85 subunit are constitutively associated 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 FYN-like kinases Reactome DB_ID: 9852271 Fyn FYN_MOUSE Reactome DB_ID: 420333 UniProt:P39688 Fyn Fyn FUNCTION Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL1 and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Phosphorylates PTK2B/PYK2 in response to T-cell receptor activation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1. In mast cells, phosphorylates CLNK after activation of immunoglobulin epsilon receptor signaling (PubMed:12681493).ACTIVITY REGULATION Inhibited by phosphorylation of Tyr-531 by leukocyte common antigen and activated by dephosphorylation of this site.SUBUNIT Interacts (via its SH3 domain) with PIK3R1 and PRMT8 (By similarity). Interacts with FYB1, PAG1, and SH2D1A (By similarity). Interacts with CD79A (tyrosine-phosphorylated form); the interaction increases FYN activity (PubMed:8168489). Interacts with TOM1L1 (phosphorylated form) (PubMed:11711534). Interacts with SH2D1A and SLAMF1 (By similarity). Interacts with and phosphorylates ITCH, down-regulating its activity (By similarity). Interacts with FASLG (By similarity). Interacts with RUNX3 (By similarity). Interacts with KIT (By similarity). Interacts with EPHA8; possible downstream effector of EPHA8 in regulation of cell adhesion (By similarity). Interacts with PTK2/FAK1; this interaction leads to PTK2/FAK1 phosphorylation and activation (By similarity). Interacts with CAV1; this interaction couples integrins to the Ras-ERK pathway (By similarity). Interacts (via SH3 domain) with KLHL2 (via N-terminus) (By similarity). Interacts with KDR (tyrosine phosphorylated) (PubMed:16966330). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:7681396, PubMed:9312046). Interacts with UNC119 (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 with FYB2 (By similarity). Interacts with DSCAM (PubMed:22685302). Interacts with SKAP1 and FYB1; this interaction promotes the phosphorylation of CLNK (PubMed:12681493).TISSUE SPECIFICITY Isoform 1 is highly expressed in the brain, isoform 2 is expressed in cells of hemopoietic lineages, especially T-lymphocytes.PTM Autophosphorylated at Tyr-420 (PubMed:8441403). Phosphorylation on the C-terminal tail at Tyr-531 by CSK maintains the enzyme in an inactive state (PubMed:8441403). PTPRC/CD45 dephosphorylates Tyr-531 leading to activation. Ultraviolet B (UVB) strongly increase phosphorylation at Thr-15 and kinase activity, and promotes translocation from the cytoplasm to the nucleus. Dephosphorylation at Tyr-420 by PTPN2 negatively regulates T-cell receptor signaling (By similarity). Phosphorylated at tyrosine residues, which can be enhanced by NTN1 (PubMed:22685302).PTM Palmitoylated (PubMed:19956733, PubMed:7980442, PubMed:8413237, PubMed:9201723). Palmitoylation at Cys-3 and Cys-6, probably by ZDHHC21, regulates subcellular location (PubMed:7980442, PubMed:8413237, PubMed:9201723, PubMed:19956733).PTM Myristoylation is required prior to palmitoylation.DISRUPTION PHENOTYPE Mice have various neural defects, including defective long term potentiation, impaired spatial memory, hypomyelination, abnormal dendrite orientation and uncoordinated hippocampal structure.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt P39688 2 EQUAL 537 EQUAL Reactome Database ID Release 82 420333 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=420333 Reactome R-MMU-420333 2 Reactome stable identifier. Use this 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-420333.2 HCK P08103 Reactome DB_ID: 9852269 UniProt:P08103 Hck Hck FUNCTION Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS (By similarity).ACTIVITY REGULATION Subject to autoinhibition, mediated by intramolecular interactions involving the SH2 and SH3 domains. Kinase activity is also regulated by phosphorylation at regulatory tyrosine residues. Phosphorylation at Tyr-409 is required for optimal activity. Phosphorylation at Tyr-520 inhibits kinase activity. Inhibited by PP1.SUBUNIT Interacts with ADAM15. Interacts with FASLG. Interacts with ARRB1 and ARRB2. Interacts with FCGR1A; the interaction may be indirect. Interacts with IL6ST. Interacts (via SH3 domain) with ELMO1. Interacts (via SH3 domain) with TP73. Interacts with YAP1. Interacts with ABL1 and ITGB1, and thereby recruits ABL1 to activated ITGB1 (By similarity). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with CBL. Interacts with VAV1, WAS and RAPGEF1. Interacts (via SH3 domain) with WDCP (By similarity).TISSUE SPECIFICITY Expressed predominantly in cells of the myeloid and B-lymphoid lineages.PTM Phosphorylated on several tyrosine residues. Autophosphorylated. Becomes rapidly phosphorylated upon activation of the immunoglobulin receptors FCGR1A and FCGR2A. Phosphorylation at Tyr-409 increases kinase activity. Phosphorylation at Tyr-520 inhibits kinase activity. Kinase activity is not required for phosphorylation at Tyr-520, suggesting that this site may be a target of other kinases.PTM Ubiquitinated by CBL, leading to its degradation via the proteasome.PTM Isoform 2 palmitoylation at position 2 requires prior myristoylation. Palmitoylation at position 3 is required for caveolar localization of isoform 2.DISRUPTION PHENOTYPE No visible phenotype, but macrophages have impaired phagocytosis. Mice lacking both HCK and FGR are extremely sensitive to infections by L.monocytogenes.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt P08103 2 EQUAL 526 EQUAL Reactome Database ID Release 82 9852269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852269 Reactome R-MMU-167708 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-167708.1 Lyn Tyrosine-protein kinase Lyn LYN_MOUSE Lyn Reactome DB_ID: 1112642 UniProt:P25911 Lyn Lyn FUNCTION Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-96'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (PubMed:28098138). Phosphorylates CLNK (PubMed:12681493).ACTIVITY REGULATION Subject to autoinhibition, mediated by intramolecular interactions between the SH2 domain and the C-terminal phosphotyrosine. Phosphorylation at Tyr-397 is required for optimal activity. Phosphorylated by CSK at Tyr-508; phosphorylation at Tyr-508 inhibits kinase activity. Kinase activity is modulated by dephosphorylation by PTPRC/CD45. Inhibited by dasatinib, PP2, and SU6656.SUBUNIT Interacts with TEC. Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with LIME1 and with CD79A upon activation of the B-cell antigen receptor. Interacts with the B-cell receptor complex. Interacts with phosphorylated THEMIS2. Interacts with EPOR. Interacts with MS4A2/FCER1B. Interaction (via the SH2 and SH3 domains) with MUC1 is stimulated by IL7 and the subsequent phosphorylation increases the binding between MUC1 and CTNNB1/beta-catenin. Interacts with ADAM15. Interacts with NDFIP2 and more weakly with NDFIP1. Interacts with FASLG. Interacts with KIT. Interacts with HCLS1. Interacts with FCGR2B. Interacts with FCGR1A; the interaction may be indirect. Interacts with CD19, CD22, CD79A and CD79B. Interacts (via SH3 domain) with CBLC, PPP1R15A and PDE4A. Interacts with TGFB1I1. Interacts (via SH3 domain) with PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase; this interaction enhances phosphatidylinositol 3-kinase activity. Interacts with CSF2RB, the common subunit of the IL3, IL5 and CSF2 receptors. Interacts with PAG1; identified in a complex with PAG1 and STAT3. Interacts with ABL1. Interacts with PTPN6/SHP-1. Interacts (via SH3 domain) with SCIMP (via proline-rich region) (PubMed:28098138). This interaction facilitates the phosphorylation of SCIMP on 'Tyr-96', which enhances binding of SCIMP to TLR4, and consequently the phosphorylation of TLR4 in response to stimulation by lipopolysaccharide in macrophages (PubMed:28098138). Interacts with LPXN (via LD motif 3) and the interaction is induced upon B-cell antigen receptor (BCR) activation. Interacts (via SH3-domain) with ANKRD54 (via ankyrin repeat region) in an activation-independent status of LYN. Forms a multiprotein complex with ANKRD54 and HCLS1. Interacts (via SH2 and SH3 domains) with UNC119; leading to LYN activation (By similarity). Interacts with CD36. Interacts with LYN (PubMed:22496641). Interacts with SKAP1 and FYB1; this interaction promotes the phosphorylation of CLNK (PubMed:12681493).TISSUE SPECIFICITY Detected in bone marrow-derived monocytes and macrophages (at protein level) (PubMed:28098138, PubMed:2017160). Expressed predominantly in B-lymphoid and myeloid cells (PubMed:2017160).DOMAIN The protein kinase domain plays an important role in its localization in the cell membrane.PTM Ubiquitinated by CBL, leading to its degradation.PTM Phosphorylated on tyrosine residues in response to KIT signaling (By similarity). Autophosphorylated. Phosphorylation at Tyr-397 is required for optimal activity. Phosphorylation at Tyr-508 inhibits kinase activity. Phosphorylated at Tyr-508 by CSK. Dephosphorylated by PTPRC/CD45. Becomes rapidly phosphorylated upon activation of the B-cell receptor and the immunoglobulin receptor FCGR1A.DISRUPTION PHENOTYPE No visible phenotype at birth. B-cell development in the bone marrow proceeds normally, but mice have reduced numbers of peripheral B-cells, with a greater proportion of immature cells and an increased turnover rate. Dendritic cells also have a more immature phenotype. Mice develop severe asthma upon exposure to airborne antigen. Mice display elevated levels of serum IgM. Aging mice display strongly increased levels of myeloid cells, severe extramedullary hematoipoiesis and tend to develop monocyte/macrophage tumors. After about 16 weeks, mice begin to develop splenomegaly and glomerulonephritis, and display autoimmune antibodies. Their B-cells are hypersensitive to stimulation of the B-cell receptor, and display enhanced activation of the MAP kinase signaling pathway. Mice do not display an allergic response upon IgE receptor engagement.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt P25911 2 EQUAL 512 EQUAL Reactome Database ID Release 82 1112642 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112642 Reactome R-MMU-1112642 2 Reactome stable identifier. Use this 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-1112642.2 SYK P48025 Reactome DB_ID: 9824234 UniProt:P48025 Syk Syk ptk72 Sykb FUNCTION Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development (PubMed:33782605). Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR also plays a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Required for the stimulation of neutrophil phagocytosis by IL15 (By similarity). Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3-mediated signaling pathway in basophils (PubMed:19098920). Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Also plays a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response (PubMed:26195794).ACTIVITY REGULATION Autoinhibited. Intramolecular binding of the interdomains A and B (also called linker region) to parts of the catalytic domain keep the catalytic center in an inactive conformation. The phosphorylation of the interdomains or the binding of the SH2 domains with dually phosphorylated ITAM domains on transmembrane proteins disrupt those intramolecular interactions allowing the kinase domain to adopt an active conformation. The phosphorylation of SYK and of the ITAM domains which is responsible for SYK activation is essentially mediated by SRC subfamily kinases, like LYN, upon transmembrane receptors engagement. May also be negatively regulated by PTPN6 through dephosphorylation (By similarity). Downstream signaling adapters and intermediates like BLNK or RHOH may mediate positive and/or negative feedback regulation. Negatively regulated by CBL and CBLB through ubiquitination and probable degradation. Phosphorylates SH3BP2 which in turn may regulate SYK through LYN (By similarity).SUBUNIT Interacts with LYN; phosphorylates SYK. Interacts with RHOH (phosphorylated); regulates mast cells activation. Interacts with NFAM1 (phosphorylated); probably involved in BCR signaling. Interacts with VAV1 (via SH2 domain); phosphorylates VAV1 upon BCR activation (By similarity). Interacts with GAB2 (phosphorylated); probably involved in IgE Fc receptor signaling. Interacts (via its SH2 domains) with CD79A (via its phosphorylated ITAM domain); the interaction stimulates SYK autophosphorylation and activation. Interacts (via SH2 domains) with FCER1G (via ITAM domain); activates SYK and mediates neutrophils and macrophages integrin-mediated activation. Interaction with FCER1G in basophils triggers IL3-induced IL4 production (PubMed:19098920). Interacts with ITGB2 and FGR; involved in ITGB2 downstream signaling. Interacts with ITGB3; upon activation by ITGB3 promotes platelet adhesion (By similarity). Interacts (via SH2 domains) with TYROBP (via ITAM domain); involved in neutrophils and macrophages integrin-mediated activation. Interacts with MSN and SELPLG; mediates the selectin-dependent activation of SYK by SELPLG (By similarity). Interacts with BLNK (via SH2 domain). Interacts (via the second SH2 domain) with USP25 (via C-terminus); phosphorylates USP25 and regulates USP25 intracellular levels (By similarity). Interacts (via SH2 domains) with CLEC1B (dimer) (By similarity). Interacts with CLEC7A; participates in leukocyte activation in presence of fungal pathogens. Interacts (phosphorylated) with SLA; may regulate SYK through CBL recruitment (By similarity). Interacts with YWHAG; attenuates BCR-induced membrane translocation and activation of SYK (By similarity). Interacts (via SH2 domains) with GCSAM; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity (By similarity). Interacts with TNS2; leading to the phosphorylation of SYK (By similarity). Interacts with FLNA (via filamin repeat 5); docks SYK to the plasma membrane (By similarity). Interacts with CEACAM1; lipopolysaccharide activated neutrophils induce phosphorylation of SYK resulting in the formation of a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, leading to a reduction of the inflammasome activity (PubMed:22496641). Interacts (via SH2 domains) with CEACAM20 (phosphorylated form); the interaction further enhances CEACAM20 phosphorylation (PubMed:26195794). Interacts with IL15RA (By similarity).DOMAIN The SH2 domains mediate the interaction of SYK with the phosphorylated ITAM domains of transmembrane proteins. Some proteins like CLEC1B have a partial ITAM domain (also called hemITAM) containing a single YxxL motif. The interaction with SYK requires CLEC1B homodimerization (By similarity).PTM Autophosphorylated. Phosphorylated on tyrosine residues by LYN following receptors engagement. Phosphorylation on Tyr-317 creates a binding site for CBL, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling. Phosphorylation at Tyr-342 creates a binding site for VAV1 (By similarity). Phosphorylation on Tyr-342 and Tyr-346 enhances the phosphorylation and activation of phospholipase C-gamma and the early phase of calcium ion mobilization via a phosphoinositide 3-kinase-independent pathway (By similarity). Phosphorylated on tyrosine residues in response to IL15 (By similarity). Phosphorylation on Ser-291 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG (By similarity). Phosphorylation at Tyr-624 creates a binding site for BLNK (By similarity). Dephosphorylated by PTPN6 (By similarity).PTM Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation.DISRUPTION PHENOTYPE Embryos display severe systemic hemorrhage and mice are not viable dying perinatally. While T-cells development is not affected, the development of B-cells is impaired most probably at the pro-B to pre-B transition and mice lack mature B-cells.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily. UniProt P48025 1 EQUAL 635 EQUAL Reactome Database ID Release 82 9824234 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9824234 Reactome R-MMU-58268 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-58268.1 YES1 Q04736 Reactome DB_ID: 9837151 UniProt:Q04736 UniProt Q04736 2 EQUAL 543 EQUAL Reactome Database ID Release 82 9837151 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9837151 Reactome R-MMU-373640 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-373640.1 Reactome Database ID Release 82 9852271 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852271 Reactome R-MMU-912625 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-912625.1 CBL P22682 Reactome DB_ID: 9830853 UniProt:P22682 UniProt P22682 1 EQUAL 906 EQUAL Reactome Database ID Release 82 9830853 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9830853 Reactome R-MMU-112199 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-112199.1 FYN-like kinases:CBL:GRB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 9852273 1 1 1 1 Reactome Database ID Release 82 9852273 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852273 Reactome R-MMU-912623 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-912623.1 Reactome Database ID Release 82 9852275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852275 Reactome R-MMU-879917 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-879917.1 Cbl is constitutively associated with Grb2 in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain can bind the adaptor protein CRKL.<br><br> Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998). <br>Cbl also associates with Fyn (Anderson et al. 1997) and the related kinases Hck and Lyn (Hunter et al. 1999). Binding studies indicate that this binding is independent of the phosphorylation state of Cbl; The association of Fyn with Cbl has been described as constitutive (Hunter et al. 1999).<br><br> Cbl further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this is also described as constitutive and is mediated by the SH3 domain of p85 (Hunter et al. 1997). 9890970 Pubmed 1999 Fyn associates with Cbl and phosphorylates tyrosine 731 in Cbl, a binding site for phosphatidylinositol 3-kinase Hunter, S Burton, EA Wu, SC Anderson, SM J Biol Chem 274:2097-106 7629144 Pubmed 1995 Specific association of the beta isoform of the p85 subunit of phosphatidylinositol-3 kinase with the proto-oncogene c-cbl Hartley, D Meisner, H Corvera, S J Biol Chem 270:18260-3 9259313 Pubmed 1997 Phosphorylation of cbl after stimulation of Nb2 cells with prolactin and its association with phosphatidylinositol 3-kinase Hunter, S Koch, BL Anderson, SM Mol Endocrinol 11:1213-22 9590251 Pubmed 1998 CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling Park, RK Kyono, WT Liu, Y Durden, DL J Immunol 160:5018-27 7537740 Pubmed 1995 The proto-oncogene product c-Cbl becomes tyrosine phosphorylated by stimulation with GM-CSF or Epo and constitutively binds to the SH3 domain of Grb2/Ash in human hematopoietic cells Odai, H Sasaki, K Iwamatsu, A Hanazono, Y Tanaka, T Mitani, K Yazaki, Y Hirai, H J Biol Chem 270:10800-5 8995358 Pubmed 1997 Phosphorylation of Cbl following stimulation with interleukin-3 and its association with Grb2, Fyn, and phosphatidylinositol 3-kinase Anderson, SM Burton, EA Koch, BL J Biol Chem 272:739-45 8621719 Pubmed 1996 p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinases, Grb2 and Shc adaptors, and the p85 subunit of phosphatidylinositol 3-kinase Panchamoorthy, G Fukazawa, T Miyake, S Soltoff, S Reedquist, K Druker, B Shoelson, S Cantley, Lewis C Band, H J Biol Chem 271:3187-94 LEFT-TO-RIGHT CBL ubiquitinates PI3K 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> FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 9852674 1 1 1 P22682 phospho-p-Y700,Y731,Y774-CBL Reactome DB_ID: 9852672 731 EQUAL 700 EQUAL 774 EQUAL 1 EQUAL 906 EQUAL Reactome Database ID Release 82 9852672 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852672 Reactome R-MMU-912656 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-912656.1 1 Reactome Database ID Release 82 9852674 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852674 Reactome R-MMU-912647 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-912647.1 K48polyUb Reactome DB_ID: 9852720 Reactome Database ID Release 82 9852720 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852720 Reactome R-MMU-912740 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-912740.1 FYN-like kinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3Ks Reactome DB_ID: 9852741 1 Converted from EntitySet in Reactome K63polyUb-p85-containing Class 1A PI3Ks Reactome DB_ID: 9852739 K63polyUb-PI3K alpha Reactome DB_ID: 9852733 1 Converted from EntitySet in Reactome K63polyUb-PI3K-regulatory subunits Reactome DB_ID: 9852731 Pik3r1 K63polyUb-PIK3R1 P26450 Reactome DB_ID: 9852723 ubiquitinylated lysine MOD MOD:01148 1 EQUAL 724 EQUAL Reactome Database ID Release 82 9852723 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852723 Reactome R-MMU-3080572 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-3080572.1 Pik3r2 K63polyUb-PIK3R2 O08908 Reactome DB_ID: 9852726 1 EQUAL 728 EQUAL Reactome Database ID Release 82 9852726 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852726 Reactome R-MMU-3080554 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-3080554.1 Pik3r3 K63polyUb-PIK3R3 Q64143 Reactome DB_ID: 9852729 1 EQUAL 461 EQUAL Reactome Database ID Release 82 9852729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852729 Reactome R-MMU-3080574 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-3080574.1 Reactome Database ID Release 82 9852731 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852731 Reactome R-MMU-3080555 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-3080555.1 1 Reactome Database ID Release 82 9852733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852733 Reactome R-MMU-3080565 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-3080565.1 K63polyUb-PI3K beta Reactome DB_ID: 9852735 1 1 Reactome Database ID Release 82 9852735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852735 Reactome R-MMU-3080558 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-3080558.1 K63polyUb-PI3K delta Reactome DB_ID: 9852737 1 1 Reactome Database ID Release 82 9852737 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852737 Reactome R-MMU-3080567 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-3080567.1 Reactome Database ID Release 82 9852739 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852739 Reactome R-MMU-3080553 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-3080553.1 1 1 1 Reactome Database ID Release 82 9852741 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852741 Reactome R-MMU-912799 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-912799.1 Reactome Database ID Release 82 9852743 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852743 Reactome R-MMU-912627 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-912627.1 Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl-B targets PI3K for ubiquitination and degradation in T cells (Fang et al. 2000). Similarly, Cbl activation by tyrosine phosphorylation increases PI3K ubiquitination and proteasomal degradation (Dufour et al. 2008). 18374639 Pubmed 2008 FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival Dufour, C Guenou, H Kaabeche, K Bouvard, D Sanjay, A Marie, PJ Bone 42:1032-9 11087752 Pubmed 2001 Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells Fang, D Wang, HY Fang, N Altman, Y Elly, C Liu, YC J Biol Chem 276:4872-8 11994499 Pubmed 2002 The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system Rao, N Dodge, I Band, H J Leukoc Biol 71:753-63 LEFT-TO-RIGHT CBL binds CRK 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 CRK, CRKL Reactome DB_ID: 9843434 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 82 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 Crk CRK Q64010 Reactome DB_ID: 9828802 UniProt:Q64010 Crk UniProt Q64010 1 EQUAL 304 EQUAL Reactome Database ID Release 82 9828802 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9828802 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 Reactome Database ID Release 82 9843434 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9843434 Reactome R-MMU-381945 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-381945.1 p(Y700,731,774)-CBL:CRK Reactome DB_ID: 9852757 1 1 Reactome Database ID Release 82 9852757 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852757 Reactome R-MMU-912774 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-912774.1 Reactome Database ID Release 82 9852782 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852782 Reactome R-MMU-912790 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-912790.1 The Crk adapter protein family is comprised of Crk-I and Crk-II, alternatively spliced products of a single gene with differing biological functions, and Crk-L, a distinct Crk-like gene product. Cbl is the dominant phosphoprotein associated with Crk in activated lymphocytes. In vitro binding indicates that the Crk SH2 domain binds Y774 of Cbl (Reedquist et al. 1996), leaving the SH3 domain of Crk free to interact with other SH3 domain-associated proteins. 8649859 Pubmed 1996 The two major sites of cbl tyrosine phosphorylation in abl-transformed cells select the crkL SH2 domain Andoniou, CE Thien, CB Langdon, WY Oncogene 12:1981-9 8626543 Pubmed 1996 Stimulation through the T cell receptor induces Cbl association with Crk proteins and the guanine nucleotide exchange protein C3G Reedquist, KA Fukazawa, T Panchamoorthy, G Langdon, WY Shoelson, SE Druker, BJ Band, H J Biol Chem 271:8435-42 LEFT-TO-RIGHT CBL:CRKL binds RAPGEF1 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> Q3UHC1 Rapgef1 RAPGEF1 Reactome DB_ID: 9829174 UniProt:Q3UHC1 Rapgef1 Rapgef1 UniProt Q3UHC1 1 EQUAL 1077 EQUAL Reactome Database ID Release 82 9829174 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829174 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 p(Y700,731,774)-CBL:CRK:RAPGEF1 Reactome DB_ID: 9852759 1 1 Reactome Database ID Release 82 9852759 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852759 Reactome R-MMU-914209 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-914209.1 Reactome Database ID Release 82 9852761 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852761 Reactome R-MMU-912734 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-912734.1 Cbl has been identified in ternary complexes with CRKL and C3G (RAPGEF1)(Reedquist et al. 1996) a Rap1 GEF, suggesting a role for Cbl in linking cytokine stimulation to Rap1 activation. Consistent with this, stimulation of NB-4 promyelocytic cells by IFN-gamma causes tyrosine phosphorylation and association of Cbl with CRKL followed by activation of Rap1 (Alsayed et al. 2000) and tyrosine phosphorylation of Cbl and its association with CRKL correlated with an increase in Rap 1 activity in anergic T cells (Boussiotis et al. 1997). 9311917 Pubmed 1997 Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1 Boussiotis, VA Freeman, GJ Berezovskaya, A Barber, DL Nadler, LM Science 278:124-8 10657627 Pubmed 2000 IFN-gamma activates the C3G/Rap1 signaling pathway Alsayed, Y Uddin, S Ahmad, S Majchrzak, B Druker, BJ Fish, EN Platanias, LC J Immunol 164:1800-6 LEFT-TO-RIGHT CBL binds VAV 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> Vav1 Proto-oncogene vav VAV_MOUSE Vav1 Reactome DB_ID: 434625 UniProt:P27870 Vav1 Vav1 Vav FUNCTION Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.SUBUNIT Interacts with SHB (By similarity). Interacts with APS, DOCK2, GRB2, GRB3, DOCK2, SLA, TEC and ZNF655/VIK. Interacts with SIAH2; without leading to its degradation. Associates with BLNK, PLCG1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB; which inhibits tyrosine phosphorylation and down-regulates activity (PubMed:10646609, PubMed:10646608). May interact with CCPG1 (PubMed:17000758). Interacts with CLNK (PubMed:11463797). Interacts with THEMIS2 (PubMed:20644716). Interacts with NEK3 and this interaction is prolactin-dependent. Interacts with ITK. Interacts with PTK2B/PYK2 (By similarity). Interacts with HCK. Interacts with PTK2B/PYK2. Interacts (via SH2 domain) with SYK (By similarity). Interacts with ANKRD54 (PubMed:19064729). Interacts with CD6 (PubMed:24584089). Interacts with isoform 2 of CRACR2A (By similarity).TISSUE SPECIFICITY Widely expressed in hematopoietic cells but not in other cell types. Found in the spleen and lung.DOMAIN The DH domain is involved in interaction with CCPG1.PTM Phosphorylated by FYN (By similarity). Phosphorylated on tyrosine residues by HCK in response to IFNG and bacterial lipopolysaccharide (LPS). UniProt P27870 1 EQUAL 845 EQUAL Reactome Database ID Release 82 434625 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434625 Reactome R-MMU-434625 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-434625.1 p(Y700,731,774)-CBL:VAV1 Reactome DB_ID: 9852753 1 1 Reactome Database ID Release 82 9852753 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852753 Reactome R-MMU-912755 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-912755.1 Reactome Database ID Release 82 9852755 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852755 Reactome R-MMU-912727 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-912727.1 Cbl and Vav interact in thymocytes and peripheral T cells (Marengere et al. 1997). Cbl phosphorylated at Y700 binds Vav1 in 293T cells, leading to Vav ubiquitinylation and proteolytic degradation. 12881521 Pubmed 2003 Cbl-mediated ubiquitinylation and negative regulation of Vav Miura-Shimura, Y Duan, L Rao, NL Reddi, AL Shimura, H Rottapel, R Druker, BJ Tsygankov, A Band, V Band, H J Biol Chem 278:38495-504 9200440 Pubmed 1997 Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells Marengère, LE Mirtsos, C Kozieradzki, I Veillette, A Mak, TW Penninger, JM J Immunol 159:70-6 Reactome Database ID Release 82 9927220 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9927220 Reactome R-MMU-912631 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-912631.1 Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl negatively regulates PI3K via this mechanism (Dufour et al. 2008). The binding of Cbl to the p85 subunit of PI3K is mediated at least in part by tyrosine phosphorylation at Y731 (Dufour et al. 2008). Fyn and the related kinases Hck and Lyn are known to be associated with Cbl (Anderson et al. 1997, Hunter et al. 1999). Fyn is proven capable of Cbl Y731 phosphorylation (Hunter et al. 1999).The association of Fyn and Cbl has been described as constitutive (Hunter et al. 1999). CBL further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this also described as constitutive and mediated by the SH3 domain of p85. Binding of the SH2 domain of p85 to a specific phosphorylation site in Cbl is postulated to explain the the increase in Cbl/p85 association seen in activated cells (Panchamoorthy et al 1996) which negatively regulates PI3K activity (Fang et al. 2001). The negative effect of increased Cbl-PI3K interaction is mediated by Y731 of Cbl. Cbl binding increases PI3K ubiquitination and proteasome degradation (Dufour et al. 2008).<br><br><br>Cbl is constitutively associated with Grb in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain binds the adaptor protein CRKL. Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998). Cbl is tyrosine phosphorylated in response to many cytokines including IL-3, IL-2 (Gesbert et al. 1998) and IL-4 (Ueno et al. 1998). 9414268 Pubmed 1998 c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidylinositol 3'-kinase pathway Ueno, H Sasaki, K Honda, H Nakamoto, T Yamagata, T Miyagawa, K Mitani, K Yazaki, Y Hirai, H Blood 91:46-53 11526404 Pubmed 2001 Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells Fang, D Liu, YC Nat Immunol 2:870-5 9461587 Pubmed 1998 Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells Gesbert, F Garbay, C Bertoglio, J J Biol Chem 273:3986-93 LEFT-TO-RIGHT IL3 stimulation induces Vav binding to Tec kinase 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> TEC P24604 Reactome DB_ID: 9837248 UniProt:P24604 Tec Tec FUNCTION Non-receptor tyrosine kinase that contributes to signaling from many receptors and participates as a signal transducer in multiple downstream pathways, including regulation of the actin cytoskeleton. Plays a redundant role to ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. Required for TCR-dependent IL2 gene induction. Phosphorylates DOK1, one CD28-specific substrate, and contributes to CD28-signaling. Mediates signals that negatively regulate IL2RA expression induced by TCR cross-linking. Plays a redundant role to BTK in BCR-signaling for B-cell development and activation, especially by phosphorylating STAP1, a BCR-signaling protein. Required in mast cells for efficient cytokine production. Involved in both growth and differentiation mechanisms of myeloid cells through activation by the granulocyte colony-stimulating factor CSF3, a critical cytokine to promoting the growth, differentiation, and functional activation of myeloid cells. Participates in platelet signaling downstream of integrin activation. Cooperates with JAK2 through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. GRB10, a negative modifier of the FOS activation pathway, is another substrate of TEC. TEC is involved in G protein-coupled receptor- and integrin-mediated signalings in blood platelets. Plays a role in hepatocyte proliferation and liver regeneration and is involved in HGF-induced ERK signaling pathway. TEC regulates also FGF2 unconventional secretion (endoplasmic reticulum (ER)/Golgi-independent mechanism) under various physiological conditions through phosphorylation of FGF2 'Tyr-82'. May also be involved in the regulation of osteoclast differentiation.ACTIVITY REGULATION Activated by tyrosine phosphorylation by a wide range of cytokine stimulations. When T-cells or B-cells receptors are activated, a series of phosphorylation leads to the recruitment of TEC to the cell membrane, where it is phosphorylated at Tyr-518. Also activated in response to SCF. Integrin engagement induces tyrosine phosphorylation of TEC in platelets. STAP1 participates in a positive feedback loop by increasing the activity of TEC. SOCS1 is an inhibitor of TEC kinase activity.SUBUNIT Interacts with INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with CD28, FASLG, FGF2, GRB10 and KIT (By similarity). Interacts with VAV1 and JAK2. Interacts with LYN.TISSUE SPECIFICITY Preferentially expressed in liver. Expression is also seen in the hematopoietic cells such as bone marrow, thymus and spleen. Lower expression is seen in the heart, kidney and ovary.DOMAIN The PH domain mediates the binding to inositol polyphosphate and phosphoinositides, leading to its targeting to the plasma membrane. It is extended in the BTK kinase family by a region designated the TH (Tec homology) domain, which consists of about 80 residues preceding the SH3 domain.DOMAIN The SH3 domain is essential for its targeting to activated CD28 costimulatory molecule.PTM Following B-cell or T-cell receptors engagement, translocates to the plasma membrane where it gets phosphorylated at Tyr-518. Undergoes also tyrosine phosphorylation during platelet activation.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. UniProt P24604 1 EQUAL 631 EQUAL Reactome Database ID Release 82 9837248 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9837248 Reactome R-MMU-912712 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-912712.1 TEC:VAV1 Reactome DB_ID: 9852264 1 1 Reactome Database ID Release 82 9852264 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852264 Reactome R-MMU-912729 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-912729.1 Reactome Database ID Release 82 9852266 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852266 Reactome R-MMU-879914 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-879914.1 IL3 stimulation induces rapid and transient tyrosine-phosphorylation of Vav and the binding of Vav to Tec kinase through Tec homology domains. (Machide et al. 1995). Vav1 and Tec were seen to associate into a complex with the activated prolactin receptor (Kline et al. 2001). These reports were interpreted as Tec enhancing Vav GEF activity, but it has been suggested that Vav might contribute to Tec activation in T cell signaling (Reynolds et al. 2002). Tec kinases generally require PI3K-dependent membrane translocation and phosphorylation of the kinase domain, often by an Src family kinase, for activation (Takesono et al. 2002). 7651724 Pubmed 1995 Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain Machide, M Mano, H Todokoro, K Oncogene 11:619-25 11328862 Pubmed 2001 Activation and association of the Tec tyrosine kinase with the human prolactin receptor: mapping of a Tec/Vav1-receptor binding site Kline, JB Moore, DJ Clevenger, CV Mol Endocrinol 15:832-41 11994416 Pubmed 2002 Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways Reynolds, LF Smyth, LA Norton, T Freshney, N Downward, J Kioussis, D Tybulewicz, VL J Exp Med 195:1103-14 12118060 Pubmed 2002 Beyond calcium: new signaling pathways for Tec family kinases Takesono, A Finkelstein, LD Schwartzberg, PL J Cell Sci 115:3039-48 LEFT-TO-RIGHT SHP1 and SHP2 bind the common beta chain 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 SHP1,SHP2 PTPN6,PTPN11 SHP-2,SHP-1 Reactome DB_ID: 9844011 PTPN11 P35235 Reactome DB_ID: 9827425 UniProt:P35235 Ptpn11 Ptpn11 FUNCTION Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus (PubMed:14967142). Positively regulates MAPK signal transduction pathway (By similarity). Dephosphorylates GAB1, ARHGAP35 and EGFR (By similarity). Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulation of its RhoA binding activity (By similarity). Dephosphorylates CDC73 (By similarity). Dephosphorylates SOX9 on tyrosine residues, leading to inactivate SOX9 and promote ossification (PubMed:29644115).SUBUNIT Interacts with CD84 and with phosphorylated SIT1 and MZPL1. Interacts with FCRL4, FCRL6 and ANKHD1. Interacts with GAREM1 (tyrosine phosphorylated); the interaction increases MAPK/ERK activity and does not affect the GRB2/SOS complex formation (By similarity). Interacts with PTPNS1 and BCAR3. Interacts with phosphorylated LIME1. Interacts with SHB and INPP5D/SHIP1. Interacts with KIR2DL1; the interaction is enhanced by ARRB2 (By similarity). Interacts with GAB2. Interacts with TERT; the interaction retains TERT in the nucleus. Interacts with PECAM1 and FER. Interacts with EPHA2 (activated); participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream signaling (By similarity). Interacts with MILR1 (tyrosine phosphorylated). Interacts with FLT1 (tyrosine-phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine-phosphorylated), KIT and GRB2. Interacts with ROS1; mediates PTPN11 phosphorylation. Interacts with PDGFRA (tyrosine phosphorylated). Interacts with PDGFRB (tyrosine phosphorylated); this interaction increases the PTPN11 phosphatase activity. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with CEACAM1 (via cytoplasmic domain); this interaction depends on the monomer/dimer equilibrium and is phosphorylation-dependent (PubMed:19948503, PubMed:9867848). Interacts with MPIG6B (via ITIM motif) (PubMed:23112346). Interacts with SIGLEC10 (PubMed:23374343). Interacts with Lilrb4a (when tyrosine phosphorylated) (PubMed:10026201). Interacts with SIGLEC10 (By similarity). Interacts with CLEC12B (via ITIM motif); this interaction triggers dephosphorylation and activation of PTPN11.TISSUE SPECIFICITY Highly expressed in brain, heart and kidney.DOMAIN The SH2 domains repress phosphatase activity. Binding of these domains to phosphotyrosine-containing proteins relieves this auto-inhibition, possibly by inducing a conformational change in the enzyme.PTM Phosphorylated on Tyr-542 and Tyr-580 upon receptor protein tyrosine kinase activation; which creates a binding site for GRB2 and other SH2-containing proteins. Phosphorylated upon activation of the receptor-type kinase FLT3. Phosphorylated by activated PDGFRB (By similarity). Phosphorylated upon activation of the receptor-type kinase PDGFRA.DISRUPTION PHENOTYPE Conditional deletion in limb and head mesenchyme leads to increased cartilage mass and deficient ossification: osteochondroprogenitors become chondrocytes and not osteoblasts caused by inability of PTPN11/SHP2 to mediate tyrosine dephosphorylation of SOX9.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily. UniProt P35235 1 EQUAL 597 EQUAL Reactome Database ID Release 82 9827425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9827425 Reactome R-MMU-162563 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-162563.1 Reactome Database ID Release 82 9844011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9844011 Reactome R-MMU-389744 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-389744.1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593,628)-Bc:SHP1, SHP2 Reactome DB_ID: 9852663 1 1 Reactome Database ID Release 82 9852663 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852663 Reactome R-MMU-914086 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-914086.1 Reactome Database ID Release 82 9852665 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852665 Reactome R-MMU-909738 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-909738.1 The common beta chain (Bc) has at least at least one direct binding site for SHP-1/SHP-2 (PTPN6/PTPN11). The SH2 domains of SHP1 and SHP2 associate with Y628 of Bc following IL-3 stimulation (Pei et al. 1994, Bone et al. 1997). SHPs act as regulators of signaling. SHP1 is thought to be a negative regulator of growth that terminates signals. Binding of SHP1 to EpoR leads to SHP1 activation and dephosphorylation of JAK2, terminating proliferative signals (Klingmuller et al. 1995). SHP1 has also been shown to interact directly and dephosphorylate JAK2 (Jiao et al. 1996). Although SHP-2 competes for the same binding site, it is thought to be a positive modulator. SHP2 associates with JAK1/2 and is phosphorylated at Y304 by these kinases, creating a GRB2 recognition motif (Yin et al. 1997). IL-3 induces the phosphorylation of SHP2 and its association with Grb2 (Welham et al. 1994). SHP2 could thereby act as an adaptor between Bc and Grb2 leading to activation of the ras/mitogen-activated protein kinase pathway. SHP2 can also associate with the p85 subunit of phosphatidylinositol 3-kinase (Welham et al. 1994) so SHP2 may also regulate this pathway. 9162089 Pubmed 1997 SHP1 and SHP2 protein-tyrosine phosphatases associate with betac after interleukin-3-induced receptor tyrosine phosphorylation. Identification of potential binding sites and substrates Bone, H Dechert, U Jirik, F Schrader, JW Welham, MJ J Biol Chem 272:14470-6 8943354 Pubmed 1996 Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1 Jiao, H Berrada, K Yang, W Tabrizi, M Platanias, LC Yi, T Mol Cell Biol 16:6985-92 7889566 Pubmed 1995 Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals Klingmüller, U Lorenz, U Cantley, Lewis C Neel, BG Lodish, HF Cell 80:729-38 7528537 Pubmed 1994 Intramolecular regulation of protein tyrosine phosphatase SH-PTP1: a new function for Src homology 2 domains Pei, D Lorenz, U Klingmüller, U Neel, BG Walsh, CT Biochemistry 33:15483-93 8995399 Pubmed 1997 Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases Yin, T Shen, R Feng, GS Yang, YC J Biol Chem 272:1032-7 7522233 Pubmed 1994 Interleukin (IL)-3 and granulocyte/macrophage colony-stimulating factor, but not IL-4, induce tyrosine phosphorylation, activation, and association of SHPTP2 with Grb2 and phosphatidylinositol 3'-kinase Welham, MJ Dechert, U Leslie, KB Jirik, F Schrader, JW J Biol Chem 269:23764-8 LEFT-TO-RIGHT 3.1.3.48 SHP1 and SHP2 dephosphorylate Y628 of IL3RB 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> High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593)-Bc:SHP1, SHP2 Reactome DB_ID: 9853460 1 Converted from EntitySet in Reactome High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593)-Bc Reactome DB_ID: 9853458 High affinity GM-CSF receptor complex dimer, inactive JAK2, p(Y593)- Bc Reactome DB_ID: 9853452 GM-CSF:GM-CSF receptor alpha subunit:p(Y593)-Bc:JAK2 Reactome DB_ID: 9853450 p(Y593)-Bc:JAK2 Reactome DB_ID: 9853448 1 P26955 phospho-Csf2rb p-Y593-CSF2RB Reactome DB_ID: 9853446 17 EQUAL 897 EQUAL Reactome Database ID Release 82 9853446 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853446 Reactome R-MMU-914092 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-914092.1 1 Reactome Database ID Release 82 9853448 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853448 Reactome R-MMU-914033 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-914033.1 1 1 Reactome Database ID Release 82 9853450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853450 Reactome R-MMU-914077 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-914077.1 2 Reactome Database ID Release 82 9853452 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853452 Reactome R-MMU-914025 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-914025.1 High affinity IL-5 receptor complex dimer, inactive JAK2, p(Y593)-Bc Reactome DB_ID: 9853456 IL5 homodimer:IL5RA:p(Y593)-Bc:JAK2 Reactome DB_ID: 9853454 1 1 Reactome Database ID Release 82 9853454 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853454 Reactome R-MMU-914069 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-914069.1 2 Reactome Database ID Release 82 9853456 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853456 Reactome R-MMU-914023 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-914023.1 Reactome Database ID Release 82 9853458 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853458 Reactome R-MMU-914054 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-914054.1 1 Reactome Database ID Release 82 9853460 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853460 Reactome R-MMU-914049 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-914049.1 ACTIVATION activeUnit: #Protein54 GENE ONTOLOGY GO:0004725 Reactome Database ID Release 82 9853461 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853461 Reactome Database ID Release 82 9853463 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853463 Reactome R-MMU-914036 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-914036.1 Synthetic phosphopeptides based on Bc were dephosphorylated by SHP1 and SHP2, peptides phosphorylated at Y628 were the best substrate followed by those phosphorylated at Y766. LEFT-TO-RIGHT 2.7.11.11 IL3RB is phosphorylated on Ser-585 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 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc Reactome DB_ID: 9852776 High affinity GM-CSF receptor complex dimer, inactive JAK2, p(S585)-Bc Reactome DB_ID: 9852770 GM-CSF:GM-CSF receptor alpha subunit:p(S585)-Common beta chain:JAK2 Reactome DB_ID: 9852768 1 p-S585-IL3RB:JAK2 Reactome DB_ID: 9852766 1 P26955 phospho-Csf2rb p-S585-CSF2RB Reactome DB_ID: 9852764 585 EQUAL O-phospho-L-serine MOD MOD:00046 17 EQUAL 897 EQUAL Reactome Database ID Release 82 9852764 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852764 Reactome R-MMU-914170 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-914170.1 1 Reactome Database ID Release 82 9852766 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852766 Reactome R-MMU-914173 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-914173.1 1 Reactome Database ID Release 82 9852768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852768 Reactome R-MMU-914178 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-914178.1 2 Reactome Database ID Release 82 9852770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852770 Reactome R-MMU-914171 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-914171.1 High affinity IL-5 receptor complex dimer, inactive JAK2, p(S585)-Common beta chain Reactome DB_ID: 9852774 IL5 homodimer:IL5RA:p(S585)-Common beta chain:JAK2 Reactome DB_ID: 9852772 1 1 Reactome Database ID Release 82 9852772 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852772 Reactome R-MMU-914169 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-914169.1 2 Reactome Database ID Release 82 9852774 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852774 Reactome R-MMU-914168 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-914168.1 Reactome Database ID Release 82 9852776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852776 Reactome R-MMU-914179 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-914179.1 ACTIVATION Prkaca mPKA alpha subunit PKA C-alpha Reactome DB_ID: 163497 UniProt:P05132 Prkaca Prkaca Pkaca FUNCTION Phosphorylates a large number of substrates in the cytoplasm and the nucleus (By similarity). Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP (PubMed:10805756, PubMed:19223768). Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (By similarity). RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts (By similarity). Involved in chondrogenesis by mediating phosphorylation of SOX9 (PubMed:10805756). Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis (By similarity). Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation (PubMed:19223768). May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity). Phosphorylates APOBEC3G and AICDA. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (By similarity).ACTIVITY REGULATION Allosterically activated by various compounds, including ATP. Activated by cAMP; the nucleotide acts as a dynamic and allosteric activator by coupling the two lobes of apo PKA, enhancing the enzyme dynamics synchronously and priming it for catalysis.SUBUNIT A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. Protein kinase A holoenzyme is comprised of two catalytic (C) and two regulatory (R) subunits which keep the enzyme in an inhibited state before activation by cyclic-AMP. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. The cAMP-dependent protein kinase catalytic subunit binds PJA2. Both isoforms 1 and 2 forms activate cAMP-sensitive PKAI and PKAII holoenzymes by interacting with regulatory subunit (R) of PKA, PRKAR1A/PKR1 and PRKAR2A/PKR2, respectively. Interacts with PRKAR1A and PRKAR2B (By similarity). Interacts with NFKB1, NFKB2 and NFKBIA in platelets; these interactions are disrupted by thrombin and collagen. Binds to ABL1 in spermatozoa and with CDC25B in oocytes. Interacts with APOBEC3G and AICDA (By similarity). Interacts with RAB13; downstream effector of RAB13 involved in tight junction assembly (By similarity). Found in a complex at least composed of MROH2B isoform 2, PRKACA isoform 2 and TCP11 (PubMed:27105888). Interacts with MROH2B isoform 2 (PubMed:27105888). Interacts with HSF1 (By similarity). Isoform 2 interacts with TCP11 (PubMed:27105888).TISSUE SPECIFICITY Isoform 2 is sperm specific.DEVELOPMENTAL STAGE Accumulates in oocytes before fertilization but fades out after fertilization.PTM Autophosphorylated. Phosphorylation is enhanced by vitamin K(2) (By similarity). Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity.PTM Asn-3 is partially deaminated to Asp-3 giving rise to 2 major isoelectric variants, called CB and CA respectively.PTM When myristoylated, Ser-11 is autophosphorylated probably in conjunction with deamidation of Asn-3.PTM Phosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficiency.DISRUPTION PHENOTYPE Frequent early postnatal lethality. Survivals are runted accompanied with mature sperm exhibiting defective forward motility.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily. UniProt P05132 2 EQUAL 351 EQUAL Reactome Database ID Release 82 163497 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163497 Reactome R-MMU-163497 2 Reactome stable identifier. Use this 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-163497.2 GENE ONTOLOGY GO:0004691 Reactome Database ID Release 82 164051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164051 Reactome Database ID Release 82 9852800 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852800 Reactome R-MMU-913451 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-913451.1 GM-CSF and IL-3 application lead to Ser-585 phosphorylation of the Common beta chain (Bc) shared with the IL-3 and IL-5 receptors (Stomski et al. 1999, Guthridge et al. 2000). PKA was identified as capable of phosphorylating Bc at S585 (Guthridge et al. 2000). 10477722 Pubmed 1999 Identification of a 14-3-3 binding sequence in the common beta chain of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors that is serine-phosphorylated by GM-CSF Stomski, FC Dottore, M Winnall, W Guthridge, MA Woodcock, J Bagley, CJ Thomas, DT Andrews, RK Berndt, MC Lopez, Angel Blood 94:1933-42 10949031 Pubmed 2000 Site-specific serine phosphorylation of the IL-3 receptor is required for hemopoietic cell survival Guthridge, MA Stomski, FC Barry, EF Winnall, W Woodcock, JM McClure, BJ Dottore, M Berndt, MC Lopez, Angel Mol Cell 6:99-108 LEFT-TO-RIGHT p-S585-IL3RB binds 14-3-3 proteins 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> Ywhaz YWHAZ P63101 Reactome DB_ID: 9820761 UniProt:P63101 Ywhaz Ywhaz 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. Induces ARHGEF7 activity on RAC1 as well as lamellipodia and membrane ruffle formation (By similarity). In neurons, regulates spine maturation through the modulation of ARHGEF7 activity (By similarity).SUBUNIT Homodimer. Heterodimerizes with YWHAE (By similarity). Homo- and heterodimerization is inhibited by phosphorylation on Ser-58 (By similarity). Interacts with FOXO4, NOXA1, SSH1 and ARHGEF2. Interacts with CDK16 and with WEE1 (C-terminal). Interacts with MLF1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with BSPRY. Interacts with Thr-phosphorylated ITGB2 (By similarity). Interacts with Pseudomonas aeruginosa exoS (unphosphorylated form). Interacts with BAX; the interaction occurs in the cytoplasm. Under stress conditions, MAPK8-mediated phosphorylation releases BAX to mitochondria. Interacts with phosphorylated RAF1; the interaction is inhibited when YWHAZ is phosphorylated on Thr-232. Interacts with TP53; the interaction enhances p53 transcriptional activity. The Ser-58 phosphorylated form inhibits this interaction and p53 transcriptional activity. Interacts with ABL1 (phosphorylated form); the interaction retains ABL1 in the cytoplasm. Interacts with PKA-phosphorylated AANAT; the interaction modulates AANAT enzymatic activity by increasing affinity for arylalkylamines and acetyl-CoA and protecting the enzyme from dephosphorylation and proteasomal degradation (By similarity). It may also prevent thiol-dependent inactivation (By similarity). Interacts with AKT1; the interaction phosphorylates YWHAZ and modulates dimerization (By similarity). Interacts with GAB2 (By similarity). Interacts with SAMSN1. Interacts with BCL2L11 and TLK2. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (By similarity). Interacts with ZFP36L1 (via phosphorylated form); this interaction occurs in a p38 MAPK- and AKT-signaling pathways (PubMed:22701344). Interacts with SLITRK1 (By similarity). Interacts with AK5, LDB1, MADD, PDE1A and SMARCB1 (By similarity). Interacts with ARHGEF7 and GIT1 (PubMed:16959763). Interacts with MEFV (By similarity).PTM The delta, brain-specific form differs from the zeta form in being phosphorylated (By similarity). Phosphorylation on Ser-184 by MAPK8; promotes dissociation of BAX and translocation of BAX to mitochondria. Phosphorylation on Thr-232; inhibits binding of RAF1 (By similarity). Phosphorylated on Ser-58 by PKA and protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion. Phosphorylation on Ser-58 by PKA; disrupts homodimerization and heterodimerization with YHAE and TP53.SIMILARITY Belongs to the 14-3-3 family. UniProt P63101 1 EQUAL 245 EQUAL Reactome Database ID Release 82 9820761 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9820761 Reactome R-MMU-206099 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-206099.1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta Reactome DB_ID: 9852778 1 1 Reactome Database ID Release 82 9852778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852778 Reactome R-MMU-914180 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-914180.1 Reactome Database ID Release 82 9852780 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852780 Reactome R-MMU-912757 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-912757.1 The common beta chain (Bc), binds 14-3-3 zeta at a site that requires phosphorylation of Serine 585 (Stomski et al. 1999). Bc modifications that prevent Ser-585 phosphorylation do not recruit 14-3-3 zeta (Guthridge et al. 2000). LEFT-TO-RIGHT 14-3-3 zeta binding allows recruitment of PI3K 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> High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta:p85-containing Class 1A PI3Ks Reactome DB_ID: 9853465 1 1 Reactome Database ID Release 82 9853465 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853465 Reactome R-MMU-914177 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-914177.1 Reactome Database ID Release 82 9853467 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853467 Reactome R-MMU-914182 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-914182.1 Immunoprecipitation and kinase activity experiments demonstrated that Ser-585 phosphorylation of the common beta chain (Bc) was required for activation of PI3K activity in response to IL-3 and co-precipitation of Bc, 14-3-3 zeta and the p85 subunit of Class 1A PI3 kinases (Guthridge et al. 2000). Subsequent experiments confirmed that Ser-585 phosphorylation and PI3K activation are required to promote cell survival in response to GM-CSF, but not for proliferation responses, and that this mechanism is independent of Bc tyrosine phosphorylation (Guthridge et al. 2004). This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors; the other involves Bc tyrosine-593 phosphorylation-mediated recruitment of SHC1, GRB2 and GAB2. 12920017 Pubmed 2004 The phosphoserine-585-dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hematopoietic cell survival through activation of NF-kappaB and induction of bcl-2 Guthridge, MA Barry, EF Felquer, FA McClure, BJ Stomski, FC Ramshaw, H Lopez, Angel Blood 103:820-7 Reactome Database ID Release 82 9927156 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9927156 Reactome R-MMU-512988 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-512988.1 GENE ONTOLOGY GO:0019221 gene ontology term for cellular process MI MI:0359 The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains.<br><br> IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009).<br><br> All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008).<br><br> The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).<br><br><br><br>Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed. 1590989 Pubmed 1992 Cytokine receptors and signal transduction Miyajima, A Kitamura, T Harada, N Yokota, T Arai, K Annu Rev Immunol 10:295-331 10450743 Pubmed 1999 Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs Blalock, WL Weinstein-Oppenheimer, C Chang, F Hoyle, PE Wang, XY Algate, PA Franklin, RA Oberhaus, SM Steelman, LS McCubrey, JA Leukemia 13:1109-66 19819937 Pubmed 2009 IL-5- and eosinophil-mediated inflammation: from discovery to therapy Kouro, T Takatsu, K Int Immunol 21:1303-9 9794243 Pubmed 1998 Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family de Groot, RP Coffer, PJ Koenderman, L Cell Signal 10:619-28 19436055 Pubmed 2009 The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease Hercus, TR Thomas, D Guthridge, MA Ekert, PG King-Scott, J Parker, MW Lopez, Angel Blood 114:1289-98 11312115 Pubmed 2001 Specificity in cytokine signal transduction: lessons learned from the IL-3/IL-5/GM-CSF receptor family Geijsen, N Koenderman, L Coffer, PJ Cytokine Growth Factor Rev 12:19-25 7896837 Pubmed 1995 A membrane proximal domain of the human interleukin-3 receptor beta c subunit that signals DNA synthesis in NIH 3T3 cells specifically binds a complex of Src and Janus family tyrosine kinases and phosphatidylinositol 3-kinase Rao, P Mufson, RA J Biol Chem 270:6886-93