BioPAX pathway converted from "Platelet activation, signaling and aggregation" in the Reactome database. Platelet activation, signaling and aggregation Platelet activation, signaling and aggregation 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> GP1b-IX-V activation signalling GP1b-IX-V activation signalling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> GP1b-IX-V binds 14-3-3-zeta GP1b-IX-V binds 14-3-3-zeta This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759854 1 plasma membrane GO 0005886 GpIb-IX-V:Collagen type I fibril:vWF [plasma membrane] GpIb-IX-V:Collagen type I fibril:vWF Reactome DB_ID: 9759846 1 GPIb-IX-V [plasma membrane] GPIb-IX-V Reactome DB_ID: 9759844 1 UniProt:O08742 Gp5 Reactome http://www.reactome.org Mus musculus NCBI Taxonomy 10090 UniProt O08742 Chain Coordinates 17 EQUAL 560 EQUAL Reactome DB_ID: 9759836 2 GPIb [plasma membrane] GPIb Reactome DB_ID: 9759834 1 UniProt:P56400 Gp1bb UniProt P56400 27 EQUAL 206 EQUAL Reactome DB_ID: 9759830 1 UniProt:O35930 Gp1ba UniProt O35930 17 EQUAL 626 EQUAL Reactome Database ID Release 78 9759836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759836 Reactome R-MMU-114667 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114667.1 Reactome DB_ID: 9759840 2 UniProt:O88186 Gp9 UniProt O88186 17 EQUAL 177 EQUAL Reactome Database ID Release 78 9759846 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759846 Reactome R-MMU-114668 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114668.1 Reactome DB_ID: 9759852 1 extracellular region GO 0005576 Collagen type I fibril:vWF [extracellular region] Collagen type I fibril:vWF Reactome DB_ID: 9759796 1 Collagen type I fibril [extracellular region] Collagen type I fibril Reactome DB_ID: 9759850 1 UniProt:Q8CIZ8 Vwf UniProt Q8CIZ8 23 EQUAL 763 EQUAL Reactome Database ID Release 78 9759852 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759852 Reactome R-MMU-114596 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114596.1 Reactome Database ID Release 78 9759854 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759854 Reactome R-MMU-435464 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-435464.1 Reactome DB_ID: 9756409 1 cytosol GO 0005829 YWHAZ dimer [cytosol] YWHAZ dimer Reactome DB_ID: 9756407 2 UniProt:P63101 Ywhaz 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 78 9756409 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9756409 Reactome R-MMU-206751 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-206751.1 Reactome DB_ID: 9783395 1 GPIb-IX-V:Collagen type I fibril:vWF:14-3-3-zeta [plasma membrane] GPIb-IX-V:Collagen type I fibril:vWF:14-3-3-zeta Reactome DB_ID: 9759854 1 Reactome DB_ID: 9756409 1 Reactome Database ID Release 78 9783395 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783395 Reactome R-MMU-429544 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-429544.1 Reactome Database ID Release 78 9783399 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783399 Reactome R-MMU-430076 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-430076.1 The Gp1b-IX-V complex binds to 14-3-3-zeta, a scaffolding protein. The highly conserved cytoplasmic domain of GpIb alpha binds directly to dimeric 14-3-3 zeta adapter protein. Binding also involves regions of GpV, and is enhanced by phosphorylation of GP1b at Ser-609 or Ser-166 of Gp1b alpha and beta respectively. For Gp1b beta this phosphorylation is PKA-dependent. 8034572 Pubmed 1994 Association of a phospholipase A2 (14-3-3 protein) with the platelet glycoprotein Ib-IX complex Du, X Harris, SJ Tetaz, TJ Ginsberg, MH Berndt, MC J Biol Chem 269:18287-90 9425086 Pubmed 1998 Binding of purified 14-3-3 zeta signaling protein to discrete amino acid sequences within the cytoplasmic domain of the platelet membrane glycoprotein Ib-IX-V complex Andrews, RK Harris, SJ McNally, T Berndt, MC Biochemistry 37:638-47 15507277 Pubmed 2004 Platelet physiology and thrombosis Andrews, RK Berndt, MC Thromb Res 114:447-53 10627461 Pubmed 2000 Cytoplasmic domains of GpIbalpha and GpIbbeta regulate 14-3-3zeta binding to GpIb/IX/V Feng, S Christodoulides, N Reséndiz, JC Berndt, MC Kroll, MH Blood 95:551-7 8631758 Pubmed 1996 Identification of a binding sequence for the 14-3-3 protein within the cytoplasmic domain of the adhesion receptor, platelet glycoprotein Ib alpha Du, X Fox, JE Pei, S J Biol Chem 271:7362-7 17897012 Pubmed 2007 Inhibition of platelet glycoprotein Ib and its antithrombotic potential Vanhoorelbeke, K Ulrichts, H Van de Walle, G Fontayne, A Deckmyn, H Curr Pharm Des 13:2684-97 inferred by electronic annotation IEA GO IEA GPIb-IX-V binding to 14-3-3 zeta is reduced by shear stress GPIb-IX-V binding to 14-3-3 zeta is reduced by shear stress This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9783395 1 Reactome DB_ID: 9759854 1 Reactome DB_ID: 9756409 1 Reactome Database ID Release 78 9783397 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783397 Reactome R-MMU-430073 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-430073.1 High shear stress, or immobilization of VWF under high shear conditions induce VWF binding to GPIb-IX-V. This activation mechanism is believed to involve shear-stress induced conformational changes in vWF. 2010539 Pubmed 1991 The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress Ikeda, Y Handa, M Kawano, K Kamata, T Murata, M Araki, Y Anbo, H Kawai, Y Watanabe, K Itagaki, I J Clin Invest 87:1234-40 inferred by electronic annotation IEA GO IEA GP1b-IX-V binds filamin GP1b-IX-V binds filamin This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759854 1 Reactome DB_ID: 9783403 1 UniProt:Q8BTM8 Flna UniProt Q8BTM8 2 EQUAL 2647 EQUAL Reactome DB_ID: 9783405 1 GPIb-IX-V:vWF:filamin-A [plasma membrane] GPIb-IX-V:vWF:filamin-A Reactome DB_ID: 9759854 1 Reactome DB_ID: 9783403 1 2 EQUAL 2647 EQUAL Reactome Database ID Release 78 9783405 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783405 Reactome R-MMU-430104 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-430104.1 Reactome Database ID Release 78 9783407 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783407 Reactome R-MMU-430096 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-430096.1 GP1b-IX-V interacts with filamin-1; within the cytoplasmic domain of GP1b alpha amino acids 557-568 and 569-579 are critical for this association. GPIb-filamin-1 association links the receptor complex to the membrane skeleton and has been proposed to regulate the ability of GPIb-IX-V to adhere to vWf under conditions of high shear. 10037692 Pubmed 1999 Glycoprotein (GP) Ib-IX-transfected cells roll on a von Willebrand factor matrix under flow. Importance of the GPib/actin-binding protein (ABP-280) interaction in maintaining adhesion under high shear Cranmer, SL Ulsemer, P Cooke, BM Salem, HH de la Salle, C Lanza, F Jackson, SP J Biol Chem 274:6097-106 11700320 Pubmed 2002 Interaction between platelet glycoprotein Ibalpha and filamin-1 is essential for glycoprotein Ib/IX receptor anchorage at high shear Williamson, D Pikovski, I Cranmer, SL Mangin, P Mistry, N Domagala, T Chehab, S Lanza, F Salem, HH Jackson, SP J Biol Chem 277:2151-9 3155520 Pubmed 1985 On the association of glycoprotein Ib and actin-binding protein in human platelets Okita, JR Pidard, D Newman, PJ Montgomery, RR Kunicki, TJ J Cell Biol 100:317-21 inferred by electronic annotation IEA GO IEA GP1b-IX-V:13-3-3-zeta complexes with p85 PI3K GP1b-IX-V:13-3-3-zeta complexes with p85 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> Reactome DB_ID: 9756235 1 UniProt:P26450 Pik3r1 Pik3r1 Pik3r1 FUNCTION Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling (By similarity). Modulates the cellular response to ER stress by promoting nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (PubMed:20348926).SUBUNIT Heterodimer of a regulatory subunit PIK3R1 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts (via SH2 domains) with CCDC88A/GIV (tyrosine-phosphorylated form); the interaction enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration (By similarity). Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (PubMed:20348926). Interacts with PIK3R2; the interaction is dissociated in an insulin-dependent manner (PubMed:20348926). Interacts with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with IRS1 and phosphorylated IRS4. Interacts with NISCH and RUFY3 (By similarity). Interacts with phosphorylated TOM1L1. Interacts with phosphorylated LIME1 upon TCR or BCR activation. Interacts with CBLB. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with SOCS7 and HCST. Interacts with AXL, FASLG, FGR, HCK, KIT and BCR. Interacts with PTK2/FAK1 (By similarity). Interacts with PDGFRB (tyrosine phosphorylated) (By similarity). Interacts with NTRK1 (phosphorylated upon ligand-binding) (By similarity). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:9312046). Interacts with FER. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated) (Probable). Interacts with PDGFRA (tyrosine phosphorylated). Interacts with LYN (via SH3 domain); this enhances enzyme activity. Interacts with ERBB4. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (By similarity). Interacts with APPL1 and APPL2 (PubMed:25328665). Interacts with SRC (By similarity). Interacts with ALOX5; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS) (By similarity).DOMAIN The SH3 domain mediates the binding to CBLB.PTM Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation.PTM Phosphorylated. Tyrosine phosphorylated in response to signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Dephosphorylated by PTPRJ. Phosphorylated by PIK3CA at Ser-608; phosphorylation is stimulated by insulin and PDGF. The relevance of phosphorylation by PIK3CA is however unclear. Phosphorylated in response to KIT and KITLG/SCF. Phosphorylated by FGR (By similarity). Phosphorylated by CSF1R. Phosphorylated by ERBB4. Phosphorylated on tyrosine residues by TEK/TIE2.SIMILARITY Belongs to the PI3K p85 subunit family. UniProt P26450 1 EQUAL 724 EQUAL Reactome DB_ID: 9783395 1 Reactome DB_ID: 9784181 1 GPIb-IX-V:vWF:14-3-3-zeta:p85 [plasma membrane] GPIb-IX-V:vWF:14-3-3-zeta:p85 Reactome DB_ID: 9756235 1 1 EQUAL 724 EQUAL Reactome DB_ID: 9783395 1 Reactome Database ID Release 78 9784181 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784181 Reactome R-MMU-443399 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-443399.1 Reactome Database ID Release 78 9784183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784183 Reactome R-MMU-443402 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-443402.1 Resting platelets contain a heterotrimeric complex of GPIb-IX-V, 14-3-3-zeta and the p85 subunit of PI-3K. While GPIb-IX-V has no apparent binding sites for PI3K so the interaction with p85 is likely to be mediated by 14-3-3-zeta. 16102041 Pubmed 2005 Platelet GPIb-IX-V-dependent signaling Ozaki, Y Asazuma, N Suzuki-Inoue, K Berndt, MC J Thromb Haemost 3:1745-51 10887121 Pubmed 2000 Phosphoinositide 3-kinase forms a complex with platelet membrane glycoprotein Ib-IX-V complex and 14-3-3zeta Munday, AD Berndt, MC Mitchell, CA Blood 96:577-84 inferred by electronic annotation IEA GO IEA GP1b signaling involves c-Src GP1b signaling involves c-Src This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9767647 1 UniProt:P05480 Src Src Src FUNCTION Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (By similarity). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (PubMed:9344858). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation (By similarity). Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus (By similarity). Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:14739300). Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation. Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-738'. Enhances DDX58/RIG-I-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr-226'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Involved in anchorage-independent cell growth (By similarity). Required for podosome formation (PubMed:21525037). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PubMed:25731159).ACTIVITY REGULATION Phosphorylation by CSK at Tyr-529 inhibits kinase activity. Inhibitory phosphorylation at Tyr-529 is enhanced by heme. Further phosphorylation by CDK1 partially reactivates CSK-inactivated SRC and facilitates complete reactivation by protein tyrosine phosphatase PTPRC. Integrin engagement stimulates kinase activity. Phosphorylation by PTK2/FAK1 enhances kinase activity. Butein and pseudosubstrate-based peptide inhibitors like CIYKYYF act as inhibitors. Phosphorylation at Tyr-418 increases kinase activity.SUBUNIT Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on integrin mediated-tyrosine phosphorylation of PTPRA (PubMed:22801373). Interacts with CDCP1, TGFB1I1 and TOM1L2 (By similarity). Interacts with DDEF1/ASAP1 via its SH3 domain (PubMed:9819391). Interacts with CCPG1 (PubMed:17000758). Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin (By similarity). Interacts with RALGPS1 via its SH3 domain (By similarity). Interacts with CAV2 (tyrosine phosphorylated form) (By similarity). Interacts (via the SH3 domain and the protein kinase domain) with ARRB1; the interaction is independent of the phosphorylation state of SRC C-terminus (By similarity). Interacts with FCAMR and PXN (By similarity). Interacts with ARRB2 (PubMed:19122674). Interacts with ARRB1 (By similarity). Interacts with SRCIN1 (By similarity). Interacts with NDFIP2 and more weakly with NDFIP1 (By similarity). Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1, ESR1 (dimethylated on arginine) and FAK (PubMed:14739300). Interacts (via SH2 and SH3 domain) with TNK2 (By similarity). Interacts (via protein kinase domain) with the tyrosine phosphorylated form of RUNX3 (via runt domain) (By similarity). Interacts with TRAF3 (via RING-type zinc finger domain) (By similarity). Interacts with DDX58, MAVS and TBK1 (By similarity). Interacts (via SH2 domain) with RACK1; the interaction is enhanced by tyrosine phosphorylation of RACK1 and inhibits SRC activity (By similarity). Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2 (PubMed:14739300). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated) (PubMed:16684964). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN (PubMed:11433297). Interacts with EPHB1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Interacts with ERBB2 and STAT1 (PubMed:7542762, PubMed:9344858). Interacts with PDGFRA (tyrosine phosphorylated) (PubMed:14644164). Interacts with CSF1R (PubMed:7681396). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 (By similarity). Interacts with DDR2 (By similarity). Interacts with AMOTL2; this interaction regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites (By similarity). Interacts with DDR1 and DAB2 (PubMed:20093046). Interacts with TRAP1 (By similarity). Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at 'Tyr-424' (By similarity). Interacts with ARHGEF5 (PubMed:21525037). Interacts (via cytoplasmic domain) with CEACAM1 (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (By similarity). Interacts with MPP2 (By similarity). Interacts with PRR7 (By similarity). Interacts (via kinase domain and to a lesser extent the SH2 domain) directly with PDLIM4; this interaction results in PTPN13-mediated dephosphorylation of this protein leading to its inactivation (By similarity). Interacts with P85 (PIK3R1 or PIK3R2) (By similarity). Interacts with HNRNPA2B1 (PubMed:31320558). Interacts with IL6ST/gp130 (By similarity). Interacts (via SH3 domain) with PELP1 in the presence of 17-beta-estradiol (By similarity).PTM Myristoylated at Gly-2, and this is essential for targeting to membranes.PTM Dephosphorylated at Tyr-529 by PTPRJ (By similarity). Phosphorylated on Tyr-529 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src. Dephosphorylated by PTPRJ at Tyr-418. Normally maintained in an inactive conformation with the SH2 domain engaged with Tyr-529, the SH3 domain engaged with the SH2-kinase linker, and Tyr-418 dephosphorylated. Dephosphorylation of Tyr-529 as a result of protein tyrosine phosphatase (PTP) action disrupts the intramolecular interaction between the SH2 domain and Tyr-529, Tyr-418 can then become autophosphorylated, resulting in SRC activation. Phosphorylation of Tyr-529 by CSK allows this interaction to reform, resulting in SRC inactivation. CDK5-mediated phosphorylation at Ser-74 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. Phosphorylated by PTK2/FAK1; this enhances kinase activity. Phosphorylated by PTK2B/PYK2; this enhances kinase activity (By similarity). Upon activation of IL6ST by IL6, Tyr-418 is phosphorylated and Tyr-529 dephosphorylated (PubMed:25731159).PTM S-nitrosylation is important for activation of its kinase activity.PTM Ubiquitinated in response to CDK5-mediated phosphorylation. Ubiquitination mediated by CBLC requires SRC autophosphorylation at Tyr-418 and may lead to lysosomal degradation (By similarity).SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt P05480 2 EQUAL 536 EQUAL Reactome DB_ID: 9759854 1 Reactome DB_ID: 9775219 1 O4'-phospho-L-tyrosine at 419 (in Homo sapiens) 419 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 2 EQUAL 536 EQUAL Reactome Database ID Release 78 9784185 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784185 Reactome R-MMU-443418 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-443418.1 Src and its downstream signaling molecule PLC gamma 2 are implicated in GPIb-IX-V (GPIbR) signalling. GPIbR-mediated platelet activation correlates with cytoskeletal association of Src, activation of PI3K and the appearance of multiple tyrosine-phosphorylated proteins (Jackson et al. 1994). von Willebrand Factor (vWF) and the vWF modulator botrocetin induce tyrosine phosphorylation of FceRIgamma, Syk, LAT and PLCgamma2. Src kinase inhibition markedly suppresses these events (Wu et al. 2001). Src and Lyn form a complex with FceRIgamma and Syk upon GPIbR/vWF interaction (Wu et al. 2003). FcgammaRIIa was tyrosine phosphorylated upon vWF and ristocetin-induced-platelet activation, followed by Syk and PLCgamma2 activation. A selective Src kinase inhibitor inhibited these events (Torti et al. 1994).<br> Though a considerable body of evidence suggests Src as a signaling molecule downstream of GPIbR the mechanism that connects Src to GPIbR is not clear. There are obvious similarities with the GPIV signal transduction pathway but also important differences: Src appears to be recruited to GPIbR upon platelet activation, while Lyn and Fyn constitutively associate with GPVI; GPVI activation induces a robust level of inositol phosphate production and PLCgamma2 activity, while GPIbRactivation PLCgamma2 activation is modest and the tyrosine phosphorylation sites of PLCgamma2 are distinct from those of GPVI stimulation (Suzuki-Inoue et al. 2004). GPVI signalling requires the FCeRIgamma chain while mouse knockouts suggest it is not required for GPIbR signalling (Kaiser-Friede et al. 2004).<br> Studies on GPIbalpha transgenic mice suggested that GPIbR activates AlphaIIbBeta3 Integrin through Src and PLC gamma2 activation (Kaiser-Friede et al. 2004). An alternative suggested mechansim is indirect association via 14-3-3-zeta and the p85 subunit of PI3K; the p85 subunit of PI3K constitutively associates with GPIbR so upon vWF/GPIb-IX-V interaction can bind Src via its SH3 domain (Wu et al. 2003).<br> Although many studies support a role for Src signaling in vWF/GPIb induced platelet activation, Src-independent platelet activation has been reported for platelets spreading on surfaces coated with echicetin, a GPIb-cross-linking component of snake venom (Navdaev & Clemetson, 2002). 14656219 Pubmed 2004 Glycoproteins VI and Ib-IX-V stimulate tyrosine phosphorylation of tyrosine kinase Syk and phospholipase Cgamma2 at distinct sites Suzuki-Inoue, K Wilde, JI Andrews, RK Auger, JM Siraganian, RP Sekiya, F Rhee, SG Watson, SP Biochem J 378:1023-9 14726383 Pubmed 2004 Signaling through GP Ib-IX-V activates alpha IIb beta 3 independently of other receptors Kasirer-Friede, A Cozzi, MR Mazzucato, M De Marco, L Ruggeri, ZM Shattil, Sanford J Blood 103:3403-11 11389024 Pubmed 2001 Role of Fc receptor gamma-chain in platelet glycoprotein Ib-mediated signaling Wu, Y Suzuki-Inoue, K Satoh, K Asazuma, N Yatomi, Y Berndt, MC Ozaki, Y Blood 97:3836-45 10224142 Pubmed 1999 Rap1B and Rap2B translocation to the cytoskeleton by von Willebrand factor involves FcgammaII receptor-mediated protein tyrosine phosphorylation Torti, M Bertoni, A Canobbio, I Sinigaglia, F Lapetina, EG Balduini, C J Biol Chem 274:13690-7 12393736 Pubmed 2003 Interaction between von Willebrand factor and glycoprotein Ib activates Src kinase in human platelets: role of phosphoinositide 3-kinase Wu, Y Asazuma, N Satoh, K Yatomi, Y Takafuta, T Berndt, MC Ozaki, Y Blood 101:3469-76 12324454 Pubmed 2002 Glycoprotein Ib cross-linking/ligation on echicetin-coated surfaces or echicetin-IgMkappa in stirred suspension activates platelets by cytoskeleton modulated calcium release Navdaev, A Clemetson, KJ J Biol Chem 277:45928-34 7523416 Pubmed 1994 Adhesion receptor activation of phosphatidylinositol 3-kinase. von Willebrand factor stimulates the cytoskeletal association and activation of phosphatidylinositol 3-kinase and pp60c-src in human platelets Jackson, SP Schoenwaelder, SM Yuan, Y Rabinowitz, I Salem, HH Mitchell, CA J Biol Chem 269:27093-9 inferred by electronic annotation IEA GO IEA c-Src binds Raf1 c-Src binds Raf1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9780469 1 UniProt:Q99N57 Raf1 UniProt Q99N57 1 EQUAL 648 EQUAL Reactome DB_ID: 9775219 1 O4'-phospho-L-tyrosine at 419 (in Homo sapiens) 419 EQUAL 2 EQUAL 536 EQUAL Reactome DB_ID: 9784187 1 Active c-Src:Raf1 [cytosol] Active c-Src:Raf1 Reactome DB_ID: 9780469 1 1 EQUAL 648 EQUAL Reactome DB_ID: 9775219 1 O4'-phospho-L-tyrosine at 419 (in Homo sapiens) 419 EQUAL 2 EQUAL 536 EQUAL Reactome Database ID Release 78 9784187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784187 Reactome R-MMU-443443 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-443443.1 Reactome Database ID Release 78 9784189 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784189 Reactome R-MMU-443439 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-443439.1 c-Src binds to Raf1, the interaction involves the SH2 and SH3 domains of c-Src and requires serine phosphorylation of Raf1. Coexpression of Raf1 and c-Src in Sf9 cells results in c-Src/Raf-1 complexes, tyrosine phosphorylation of Raf-1, and stimulation of Raf-1 kinase activity. Tyr-340 and Tyr-341 were found to be the major tyrosine phosphorylation sites of Raf1 when coexpressed with activated tyrosine kinases. However, the significance of tyrosine phosphorylation under physiological conditions remains unclear, as tyrosine phosphorylation of endogenous Raf-1 following activation has been disputed and may be limited to cells of hematopoietic origin. 7517401 Pubmed 1994 Raf-1 interacts with Fyn and Src in a non-phosphotyrosine-dependent manner Cleghon, V Morrison, Deborah K J Biol Chem 269:17749-55 7692235 Pubmed 1993 Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase Fabian, JR Daar, IO Morrison, Deborah K Mol Cell Biol 13:7170-9 18494562 Pubmed 2008 Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila Xia, F Li, J Hickey, GW Tsurumi, A Larson, K Guo, D Yan, SJ Silver-Morse, L Li, WX PLoS Biol 6:e128 9171352 Pubmed 1997 Activation of c-Raf-1 by Ras and Src through different mechanisms: activation in vivo and in vitro Stokoe, D McCormick, F EMBO J 16:2384-96 inferred by electronic annotation IEA GO IEA 14-3-3-zeta binds Raf1 14-3-3-zeta binds Raf1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9780469 1 1 EQUAL 648 EQUAL Reactome DB_ID: 9756409 1 Reactome DB_ID: 9784210 1 14-3-3-zeta:Raf1 [cytosol] 14-3-3-zeta:Raf1 Reactome DB_ID: 9780469 1 1 EQUAL 648 EQUAL Reactome DB_ID: 9756409 1 Reactome Database ID Release 78 9784210 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784210 Reactome R-MMU-443827 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-443827.1 Reactome Database ID Release 78 9784212 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784212 Reactome R-MMU-443831 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-443831.1 14-3-3 family proteins can bind Raf1 and have been suggested to activate Raf1, but this has been refuted. 7935795 Pubmed 1994 Activation of Raf-1 by 14-3-3 proteins Fantl, WJ Muslin, AJ Kikuchi, A Martin, JA MacNicol, AM Gross, RW Williams, LT Nature 371:612-4 7760835 Pubmed 1995 14-3-3 is not essential for Raf-1 function: identification of Raf-1 proteins that are biologically activated in a 14-3-3- and Ras-independent manner Michaud, NR Fabian, JR Mathes, KD Morrison, Deborah K Mol Cell Biol 15:3390-7 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861792 Reactome R-MMU-430116 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-430116.1 The platelet GPIb complex (GP1b-IX-V) together with GPVI are primarily responsible for regulating the initial adhesion of platelets to the damaged blood vessel and platelet activation. The importance of GPIb is demonstrated by the bleeding problems in patients with Bernard-Soulier syndrome where this receptor is either absent or defective. GP1b-IX-V binds von Willebrand Factor (vWF) to resting platelets, particularly under conditions of high shear stress. This transient interaction is the first stage of the vascular repair process. Activation of GP1b-IX-V on exposure of the fibrous matrix following atherosclerotic plaque rupture, or in occluded arteries, is a major contributory factor leading to thrombus formation leading to heart attack or stroke. GpIb also binds thrombin (Yamamoto et al. 1986), at a site distinct from the site of vWF binding, acting as a docking site for thrombin which then activates Proteinase Activated Receptors leading to enhanced platelet activation (Dormann et al. 2000). 11001899 Pubmed 2000 The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity Dörmann, D Clemetson, KJ Kehrel, BE Blood 96:2469-78 2424116 Pubmed 1986 Localization of a thrombin-binding site on human platelet membrane glycoprotein Ib determined by a monoclonal antibody Yamamoto, K Yamamoto, N Kitagawa, H Tanoue, K Kosaki, G Yamazaki, H Thromb Haemost 55:162-7 17597991 Pubmed 2007 Von Willebrand factor: looking back and looking forward Ruggeri, ZM Thromb Haemost 98:55-62 17585075 Pubmed 2007 Adhesion mechanisms in platelet function Ruggeri, ZM Mendolicchio, GL Circ Res 100:1673-85 inferred by electronic annotation IEA GO IEA Signal amplification Signal amplification 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> ADP signalling through P2Y purinoceptor 12 ADP signalling through P2Y purinoceptor 12 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> P2RY12 binds ADP P2RY12 binds ADP This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 114564 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 9778144 1 UniProt:Q9CPV9 P2ry12 UniProt Q9CPV9 1 EQUAL 342 EQUAL Reactome DB_ID: 9778146 1 P2RY12:ADP [plasma membrane] P2RY12:ADP Reactome DB_ID: 114564 1 Reactome DB_ID: 9778144 1 1 EQUAL 342 EQUAL Reactome Database ID Release 78 9778146 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9778146 Reactome R-MMU-417834 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-417834.1 Reactome Database ID Release 78 9781079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781079 Reactome R-MMU-417829 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-417829.1 P2RY12 (Bodor et al. 2003) is found on the surface of blood platelet cells and is an important regulator in blood clotting. It is one of two ADP receptors expressed in platelets, the other is P2RY1. Activation leads to irreversible platelet aggregation. Defects in this receptor are associated with bleeding disorders. Its preferred ligand is ADP. The platelet anticoagulant drug clopidogrel binds to this receptor (Hollopeter G et al. 2001). 14573771 Pubmed 2003 Purification and functional reconstitution of the human P2Y12 receptor Bodor, ET Waldo, GL Hooks, SB Corbitt, J Boyer, JL Harden, TK Mol Pharmacol 64:1210-6 11196645 Pubmed 2001 Identification of the platelet ADP receptor targeted by antithrombotic drugs Hollopeter, G Jantzen, HM Vincent, D Li, G England, L Ramakrishnan, V Yang, RB Nurden, P Nurden, A Julius, D Conley, PB Nature 409:202-7 12560222 Pubmed 2003 Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270 Ding, Z Kim, S Dorsam, RT Jin, J Kunapuli, SP Blood 101:3908-14 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 78 9781080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781080 Reactome DB_ID: 9781077 P2RY12:P2RY12 antagonists [plasma membrane] P2RY12:P2RY12 antagonists Converted from EntitySet in Reactome Reactome DB_ID: 9611319 1 P2RY12 antagonists [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity R-138727 [extracellular region] cangrelor [extracellular region] ticagrelor [extracellular region] clopidogrel [extracellular region] ticlopidine [extracellular region] Guide to Pharmacology 1771 Guide to Pharmacology 1776 Guide to Pharmacology 1765 Guide to Pharmacology 1772 Guide to Pharmacology 7307 Reactome DB_ID: 9778144 1 1 EQUAL 342 EQUAL Reactome Database ID Release 78 9781077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781077 Reactome R-MMU-9611315 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9611315.1 Activated P2Y purinoceptor 12 binds G-protein Gi Activated P2Y purinoceptor 12 binds G-protein Gi This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9778544 1 Heterotrimeric G-protein Gi (inactive) [plasma membrane] Heterotrimeric G-protein Gi (inactive) Reactome DB_ID: 9764517 1 G-protein alpha (i):GDP [plasma membrane] G-protein alpha (i):GDP Reactome DB_ID: 114549 1 GDP [ChEBI:17552] GDP Guanosine 5'-diphosphate Guanosine diphosphate ChEBI 17552 Converted from EntitySet in Reactome Reactome DB_ID: 9764495 1 G alpha (i) [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Gnai3 [plasma membrane] Gnai1 [plasma membrane] Gnat3 [plasma membrane] Gnai2 [plasma membrane] UniProt Q9DC51 UniProt B2RSH2 UniProt Q3V3I2 UniProt P08752 Reactome Database ID Release 78 9764517 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764517 Reactome R-MMU-392164 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392164.1 Reactome DB_ID: 9759174 1 G-protein beta-gamma complex [plasma membrane] G-protein beta-gamma complex Converted from EntitySet in Reactome Reactome DB_ID: 9759165 1 G-protein gamma subunit [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity G-protein gamma 2 subunit [plasma membrane] UniProt P63213 Converted from EntitySet in Reactome Reactome DB_ID: 9759172 1 G-protein beta subunit [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity G-protein beta 1 subunit [cytosol] UniProt P62874 Reactome Database ID Release 78 9759174 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759174 Reactome R-MMU-167434 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167434.1 Reactome Database ID Release 78 9778544 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9778544 Reactome R-MMU-392165 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392165.1 Reactome DB_ID: 9778146 1 Reactome DB_ID: 9780366 1 ADP:P2RY12:G-protein Gi (inactive) [plasma membrane] ADP:P2RY12:G-protein Gi (inactive) Reactome DB_ID: 9778544 1 Reactome DB_ID: 9778146 1 Reactome Database ID Release 78 9780366 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780366 Reactome R-MMU-392184 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392184.1 Reactome Database ID Release 78 9780368 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780368 Reactome R-MMU-392187 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392187.1 The activated receptor binds the inactive, GDP-bound form of the heterotrimeric G-protein Gi. inferred by electronic annotation IEA GO IEA Gi activation by P2Y purinoceptor 12 Gi activation by P2Y purinoceptor 12 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9780366 1 Reactome DB_ID: 29438 1 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI 37565 Reactome DB_ID: 29420 1 GDP(3-) [ChEBI:58189] GDP(3-) guanosine 5'-diphosphate(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate trianion GDP GDP trianion guanosine 5'-diphosphate ChEBI 58189 Reactome DB_ID: 9780370 1 ADP:P2RY12:G-protein Gi (active) [plasma membrane] ADP:P2RY12:G-protein Gi (active) Reactome DB_ID: 9778548 1 Heterotrimeric G-protein Gi (active) [plasma membrane] Heterotrimeric G-protein Gi (active) Reactome DB_ID: 9764497 1 G alpha (i): GTP [plasma membrane] G alpha (i): GTP Converted from EntitySet in Reactome Reactome DB_ID: 9764495 1 Reactome DB_ID: 29438 1 Reactome Database ID Release 78 9764497 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9764497 Reactome R-MMU-392161 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392161.1 Reactome DB_ID: 9759174 1 Reactome Database ID Release 78 9778548 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9778548 Reactome R-MMU-392168 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392168.1 Reactome DB_ID: 9778146 1 Reactome Database ID Release 78 9780370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780370 Reactome R-MMU-392194 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392194.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9780366 GO 0005085 GO molecular function Reactome Database ID Release 78 9780371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780371 Reactome Database ID Release 78 9780373 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780373 Reactome R-MMU-392195 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392195.1 The G-protein alpha subunit exchanges GDP for GTP 8554519 Pubmed 1995 The human platelet ADP receptor activates Gi2 proteins Ohlmann, P Laugwitz, KL Nurnberg, B Spicher, K Schultz, G Cazenave, JP Gachet, C Biochem J 312:775-9 inferred by electronic annotation IEA GO IEA Dissociation of the P2Y purinoceptor 12:Gi complex Dissociation of the P2Y purinoceptor 12:Gi 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> Reactome DB_ID: 9780370 1 Reactome DB_ID: 9764497 1 Reactome DB_ID: 114564 1 Reactome DB_ID: 9759174 1 Reactome DB_ID: 9778144 1 1 EQUAL 342 EQUAL Reactome Database ID Release 78 9780375 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780375 Reactome R-MMU-392202 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392202.1 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). 18577758 Pubmed 2008 Dissociation of heterotrimeric g proteins in cells Lambert, NA Sci Signal 1:re5 8736705 Pubmed 1996 GTP binding to Gs does not promote subunit dissociation Basi, NS Okuya, S Rebois, RV Cell Signal 8:209-15 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861664 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861664 Reactome R-MMU-392170 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392170.1 GO 0030168 GO biological process Co-activation of P2Y1 and P2Y12 is necessary for complete platelet activation. P2Y1 is coupled to Gq and helps trigger the release of calcium from internal stores, leading to weak and reversible platelet aggregation. P2Y12 is Gi coupled, inhibiting adenylate cyclase, leading to decreased cAMP, a consequent decrease in cAMP-dependent protein kinase activity which increases cytoplasmic [Ca2+], necessary for activation (Woulfe et al. 2001).<br> In activated platelets, P2Y12 signaling is required for the amplification of aggregation induced by all platelet agonists including collagen, thrombin, thromboxane, adrenaline and serotonin. P2Y12 activation causes potentiation of thromboxane generation, secretion leading to irreversible platelet aggregation and thrombus stabilization. 16466948 Pubmed 2006 The platelet P2 receptors in arterial thrombosis Gachet, C Léon, C Hechler, B Blood Cells Mol Dis 36:223-7 11413156 Pubmed 2001 ADP and platelets: the end of the beginning Woulfe, D Yang, J Brass, L J Clin Invest 107:1503-5 inferred by electronic annotation IEA GO IEA ADP signalling through P2Y purinoceptor 1 ADP signalling through P2Y purinoceptor 1 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> P2RY1 binds ADP P2RY1 binds ADP This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 114564 1 Reactome DB_ID: 9777530 1 UniProt:P49650 P2ry1 UniProt P49650 1 EQUAL 373 EQUAL Reactome DB_ID: 9777532 1 P2RY1:ADP [plasma membrane] P2RY1:ADP Reactome DB_ID: 114564 1 Reactome DB_ID: 9777530 1 1 EQUAL 373 EQUAL Reactome Database ID Release 78 9777532 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9777532 Reactome R-MMU-417920 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-417920.1 Reactome Database ID Release 78 9781094 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781094 Reactome R-MMU-417908 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-417908.1 P2RY1 binds ADP (Leon et al. 1996). It is one of two platelet ADP receptors, the other is P2RY12, that initiate platelet activation when stimulated in concert. P2RY1 signals through Gq, while P2Y12 signals through Gi. This results in mobilization of intracellular calcium ions via activation of phospholipase C, which leads to a change in platelet shape and probably to platelet aggregation (Schachter et al. 1997). 9364473 Pubmed 1997 HEK293 human embryonic kidney cells endogenously express the P2Y1 and P2Y2 receptors Schachter, JB Sromek, SM Nicholas, RA Harden, TK Neuropharmacology 36:1181-7 8666290 Pubmed 1996 Cloning and sequencing of a human cDNA encoding endothelial P2Y1 purinoceptor Léon, C Vial, C Cazenave, JP Gachet, C Gene 171:295-7 inferred by electronic annotation IEA GO IEA Dissociation of the P2Y purinoceptor 1:Gq complex Dissociation of the P2Y purinoceptor 1:Gq 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> Reactome DB_ID: 9781265 1 ADP:P2RY1:G-protein Gq (active) [plasma membrane] ADP:P2RY1:G-protein Gq (active) Reactome DB_ID: 9777532 1 Reactome DB_ID: 9759176 1 G protein-GTP [plasma membrane] G protein-GTP Reactome DB_ID: 9758872 1 G protein alpha:GTP complex [plasma membrane] G protein alpha:GTP complex Converted from EntitySet in Reactome Reactome DB_ID: 9758870 1 G-protein alpha (q/11/14/15) [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Gna14 [plasma membrane] Gna11 [plasma membrane] Gnaq [plasma membrane] Gna15 [plasma membrane] UniProt P30677 UniProt P21278 UniProt P21279 UniProt P30678 Reactome DB_ID: 29438 1 Reactome Database ID Release 78 9758872 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9758872 Reactome R-MMU-167438 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167438.1 Reactome DB_ID: 9759174 1 Reactome Database ID Release 78 9759176 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759176 Reactome R-MMU-167439 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-167439.1 Reactome Database ID Release 78 9781265 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781265 Reactome R-MMU-418575 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418575.1 Reactome DB_ID: 9758872 1 Reactome DB_ID: 114564 1 Reactome DB_ID: 9759174 1 Reactome DB_ID: 9777530 1 1 EQUAL 373 EQUAL Reactome Database ID Release 78 9781267 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781267 Reactome R-MMU-418576 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418576.1 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). inferred by electronic annotation IEA GO IEA Src activation following P2Y purinoceptor activation Src activation following P2Y purinoceptor activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9767647 1 2 EQUAL 536 EQUAL Reactome DB_ID: 9775219 1 O4'-phospho-L-tyrosine at 419 (in Homo sapiens) 419 EQUAL 2 EQUAL 536 EQUAL Reactome Database ID Release 78 9781299 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781299 Reactome R-MMU-418662 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418662.1 Activation of Src lies selectively downstream of P2Y1, but not P2Y12. The precise mechanism is not known, but Src regulation of the PI3K component of the intracellular calcium response downstream of P2Y12 represents a point of reciprocal cross-talk between P2Y1 and P2Y12 receptors. 15187029 Pubmed 2004 Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium signaling in human platelets Hardy, AR Jones, ML Mundell, SJ Poole, AW Blood 104:1745-52 inferred by electronic annotation IEA GO IEA 3.6.5.4 3.6.5.3 3.6.5.2 3.6.5.1 P2Y purinoceptor 1 activates MAP kinase p38 alpha P2Y purinoceptor 1 activates MAP kinase p38 alpha This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 448843 1 UniProt:P47811 Mapk14 Mapk14 Csbp2 Mapk14 Crk1 Csbp1 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Phosphorylates S100A9 at 'Thr-113' (By similarity).ACTIVITY REGULATION Activated by cell stresses such as DNA damage, heat shock, osmotic shock, anisomycin and sodium arsenite, as well as pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) and interleukin-1. Activation occurs through dual phosphorylation of Thr-180 and Tyr-182 by either of two dual specificity kinases, MAP2K3/MKK3 or MAP2K6/MKK6, and potentially also MAP2K4/MKK4, as well as by TAB1-mediated autophosphorylation. MAPK14 phosphorylated on both Thr-180 and Tyr-182 is 10-20-fold more active than MAPK14 phosphorylated only on Thr-180, whereas MAPK14 phosphorylated on Tyr-182 alone is inactive. whereas Thr-180 is necessary for catalysis, Tyr-182 may be required for auto-activation and substrate recognition. Phosphorylated at Tyr-323 by ZAP70 in an alternative activation pathway in response to TCR signaling in T-cells. This alternative pathway is inhibited by GADD45A. Inhibited by dual specificity phosphatases, such as DUSP1, DUSP10, and DUSP16. Specifically inhibited by the binding of pyridinyl-imidazole compounds, which are cytokine-suppressive anti-inflammatory drugs (CSAID). SB203580 is an inhibitor of MAPK14.SUBUNIT Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (By similarity). Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR (By similarity). This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation (By similarity). Interacts with SPAG9 and GADD45A (By similarity). Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B. Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14 and may regulate its dephosphorylation (By similarity).TISSUE SPECIFICITY Macrophages, monocytes, T- and B-lymphocytes. Isoform 2 is specifically expressed in kidney and liver.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory cytokines, environmental stress or growth factors, which activates the enzyme. Dual phosphorylation can also be mediated by TAB1-mediated autophosphorylation. TCR engagement in T-cells also leads to Tyr-323 phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1, DUSP10 and DUSP16. PPM1D also mediates dephosphorylation and inactivation of MAPK14 (By similarity).PTM Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity. Lys-53 and Lys-152 are deacetylated by HDAC3 (By similarity).PTM Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway (By similarity).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt P47811 2 EQUAL 360 EQUAL Reactome DB_ID: 113592 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 29370 2 Reactome DB_ID: 448842 1 O-phospho-L-threonine at 180 180 EQUAL O-phospho-L-threonine [MOD:00047] O4'-phospho-L-tyrosine at 182 182 EQUAL 2 EQUAL 360 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9758872 GO 0003924 GO molecular function Reactome Database ID Release 78 9781268 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781268 Reactome Database ID Release 78 9782905 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782905 Reactome R-MMU-428941 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428941.1 ADP activates human platelets and induces endothelial cell migration. These effects are partly mediated by the P2Y1 purinocetor, inducing p38 MAP kinase activation via an uncharacterised factor. Possible mechanisms include flotillin-mediated stimulation of SRC family kinases in lipid rafts (Sugawara et al. 2007). 18174464 Pubmed 2008 ADP stimulates human endothelial cell migration via P2Y1 nucleotide receptor-mediated mitogen-activated protein kinase pathways Shen, Jinlong DiCorleto, PE Circ Res 102:448-56 17307333 Pubmed 2007 The lipid raft proteins flotillins/reggies interact with Galphaq and are involved in Gq-mediated p38 mitogen-activated protein kinase activation through tyrosine kinase Sugawara, Y Nishii, H Takahashi, T Yamauchi, J Mizuno, N Tago, K Itoh, H Cell Signal 19:1301-8 10759852 Pubmed 2000 The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human platelets Dangelmaier, C Jin, J Daniel, JL Smith, JB Kunapuli, SP Eur J Biochem 267:2283-9 inferred by electronic annotation IEA GO IEA 2.7.11 Phosphorylation of cPLA2 by MAPK p38 alpha Phosphorylation of cPLA2 by MAPK p38 alpha This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9782907 1 UniProt:P47713 Pla2g4a UniProt P47713 1 EQUAL 749 EQUAL Reactome DB_ID: 29370 2 Reactome DB_ID: 9758883 1 endoplasmic reticulum membrane GO 0005789 O-phospho-L-serine at 505 (in Homo sapiens) 505 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 727 (in Homo sapiens) 727 EQUAL 1 EQUAL 749 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 448842 O-phospho-L-threonine at 180 180 EQUAL O4'-phospho-L-tyrosine at 182 182 EQUAL 2 EQUAL 360 EQUAL GO 0004674 GO molecular function Reactome Database ID Release 78 9782908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782908 Reactome Database ID Release 78 9782910 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782910 Reactome R-MMU-428961 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428961.1 MAPK p38 alpha activates cPLA2 by phosphorylation of two serine residues.<br>cPLA2 can be phosphorylated and activated by ERK2 (Lin et al. 1993), and were believed to be responsible for the phosphorylation of cPLA2. However, phosphorylation of cPLA2 occurred in the absence of ERK activation in human platelets stimulated with the thrombin receptor agonist peptide SFLLRN (Kramer et al. 1995), and cPLA2 phosphorylation induced by thrombin or collagen was unaffected by PKC inhibitors that prevent ERK activation (Börsch-Haubold et al. 1995). In addition, a specific inhibitor of ERKs did not block thrombin-induced cPLA2 phosphorylation (Börsch-Haubold et al. 1996). 7592775 Pubmed 1995 Cytosolic phospholipase A2 is phosphorylated in collagen- and thrombin-stimulated human platelets independent of protein kinase C and mitogen-activated protein kinase Börsch-Haubold, AG Kramer, RM Watson, SP J Biol Chem 270:25885-92 9468497 Pubmed 1998 Identification of the phosphorylation sites of cytosolic phospholipase A2 in agonist-stimulated human platelets and HeLa cells Börsch-Haubold, AG Bartoli, F Asselin, J Dudler, T Kramer, RM Apitz-Castro, R Watson, SP Gelb, Michael H J Biol Chem 273:4449-58 8381049 Pubmed 1993 cPLA2 is phosphorylated and activated by MAP kinase Lin, LL Wartmann, M Lin, AY Knopf, JL Seth, A Davis, RJ Cell 72:269-78 8910365 Pubmed 1996 p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2 Kramer, RM Roberts, EF Um, SL Börsch-Haubold, AG Watson, SP Fisher, MJ Jakubowski, JA J Biol Chem 271:27723-9 8761473 Pubmed 1996 Inhibition of mitogen-activated protein kinase kinase does not impair primary activation of human platelets Börsch-Haubold, AG Kramer, RM Watson, SP Biochem J 318:207-12 7782348 Pubmed 1995 Differential activation of cytosolic phospholipase A2 (cPLA2) by thrombin and thrombin receptor agonist peptide in human platelets. Evidence for activation of cPLA2 independent of the mitogen-activated protein kinases ERK1/2 Kramer, RM Roberts, EF Hyslop, PA Utterback, BG Hui, KY Jakubowski, JA J Biol Chem 270:14816-23 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861710 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861710 Reactome R-MMU-418592 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418592.1 Co-activation of P2Y1 and P2Y12 is necessary for complete platelet activation. P2Y1 is coupled to Gq and helps trigger the release of calcium from internal stores, leading to weak and reversible platelet aggregation. P2Y12 is Gi coupled, inhibiting adenylate cyclase, leading to decreased cAMP, a consequent decrease in cAMP-dependent protein kinase activity which increases cytoplasmic [Ca2+], necessary for activation (Woulfe et al. 2001).<br> In activated platelets, P2Y12 signaling is required for the amplification of aggregation induced by all platelet agonists including collagen, thrombin, thromboxane, adrenaline and serotonin. P2Y12 activation causes potentiation of thromboxane generation, secretion leading to irreversible platelet aggregation and thrombus stabilization. 9442040 Pubmed 1998 Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets Jin, J Daniel, JL Kunapuli, SP J Biol Chem 273:2030-4 inferred by electronic annotation IEA GO IEA Thromboxane signalling through TP receptor Thromboxane signalling through TP 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> AAMP binds to TBXA2R AAMP binds to TBXA2R This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9777578 1 UniProt:P30987 Tbxa2r UniProt P30987 1 EQUAL 343 EQUAL Reactome DB_ID: 9858271 1 UniProt:J3QN89 Aamp UniProt J3QN89 1 EQUAL 434 EQUAL Reactome DB_ID: 9858275 1 TBXA2R-alpha,TBXA2R-beta:AAMP [plasma membrane] TBXA2R-alpha,TBXA2R-beta:AAMP Reactome DB_ID: 9777578 1 1 EQUAL 343 EQUAL Reactome DB_ID: 9858271 1 1 EQUAL 434 EQUAL Reactome Database ID Release 78 9858275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9858275 Reactome R-MMU-9674871 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9674871.1 Reactome Database ID Release 78 9858277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9858277 Reactome R-MMU-9674529 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9674529.1 AAMP (Angio-associated migratory cell protein) binds to both the TP-alpha and TP-beta isoforms which arise due to differential splicing of a primary RNA transcript encoded by the TBXA2R (thromboxane A2 receptor) gene. Their association with AAMP is dependent on common (residues 312-328) and unique (residues 366-392 of TP-beta) sequences within the variant carboxyl-terminal domains of TP-alpha and TP-beta. Stimulation of the TPs with U46619, a stable mimetic of thromboxane (TX) A2, leads to a transient dissociation of AAMP from both the TP-alpha nad TP-beta isoforms, coinciding with a transient redistribution of AAMP from its localization in an intracellular fibrous network. Down-regulation of AAMP reduces coronary artery smooth muscle migration, an effect that is further enhanced in the presence of U46619, while VEGF-mediated migration is not affected. AAMP and TXA2 can independently activate RHOA signaling. (Reid et al. 2011). 21172430 Pubmed 2011 Interaction of angio-associated migratory cell protein with the TPα and TPβ isoforms of the human thromboxane A₂ receptor Reid, Helen M Wikström, Katarina Kavanagh, David J Mulvaney, Eamon P Kinsella, B Therese Cell. Signal. 23:700-17 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 78 9674874 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9674874 Reactome DB_ID: 391932 thromboxane A2 [ChEBI:15627] thromboxane A2 ChEBI 15627 TP receptor can bind thromboxane TP receptor can bind thromboxane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 391932 1 Reactome DB_ID: 9777578 1 1 EQUAL 343 EQUAL Reactome DB_ID: 9777580 1 TBXA2R:TXA2 [plasma membrane] TBXA2R:TXA2 Reactome DB_ID: 391932 1 Reactome DB_ID: 9777578 1 1 EQUAL 343 EQUAL Reactome Database ID Release 78 9777580 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9777580 Reactome R-MMU-391925 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-391925.1 Reactome Database ID Release 78 9780288 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780288 Reactome R-MMU-391939 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-391939.1 Thromboxane (TBXA2) is a potent stimulator for platelet aggregation and clot formation and also plays a role in vascular tone. The thromboxane receptor TP (Hirata et al. 1991) is found on the surface of vascular endothelium, platelets and in the placenta. Once bound to its ligand, TP's effects are mediated via coupling to G q/11 activation of a phosphatidylinositol-calcium second messenger system (Kinsella BT et al, 1997). TP signaling also involves G12/13 signaling; selective activation of G12/13 results in dense granule release in a mechanism that is independent of Gq/phospholipase C. The downstream mechanism for this is thought to be RhoA mediated activation of PKCdelta, as PAR-mediated dense granule release is inhibited if RhoA is blocked, and RhoA regulates PKCdelta T505 phosphorylation (Jin et al. 2009). 9152406 Pubmed 1997 The human thromboxane A2 receptor alpha isoform (TP alpha) functionally couples to the G proteins Gq and G11 in vivo and is activated by the isoprostane 8-epi prostaglandin F2 alpha Kinsella, BT O'Mahony, DJ FitzGerald, GA J Pharmacol Exp Ther 281:957-64 19073150 Pubmed 2009 RhoA downstream of G(q) and G(12/13) pathways regulates protease-activated receptor-mediated dense granule release in platelets Jin, J Mao, Y Thomas, D Kim, S Daniel, JL Kunapuli, SP Biochem Pharmacol 77:835-44 1825698 Pubmed 1991 Cloning and expression of cDNA for a human thromboxane A2 receptor Hirata, M Hayashi, Y Ushikubi, F Yokota, Y Kageyama, R Nakanishi, S Narumiya, S Nature 349:617-20 inferred by electronic annotation IEA GO IEA Activated TP receptor binds G-proten Gq Activated TP receptor binds G-proten Gq This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759685 1 Heterotrimeric G-protein Gq/11 (inactive) [plasma membrane] Heterotrimeric G-protein Gq/11 (inactive) Reactome DB_ID: 9759683 1 G-protein alpha (q/11):GDP [plasma membrane] G-protein alpha (q/11):GDP Reactome DB_ID: 114549 1 Converted from EntitySet in Reactome Reactome DB_ID: 9758870 1 Reactome Database ID Release 78 9759683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759683 Reactome R-MMU-114556 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114556.1 Reactome DB_ID: 9759174 1 Reactome Database ID Release 78 9759685 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759685 Reactome R-MMU-114557 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114557.1 Reactome DB_ID: 9777580 1 Reactome DB_ID: 9782866 1 TP receptor:Thromboxane A2:G-protein Gq (inactive) [plasma membrane] TP receptor:Thromboxane A2:G-protein Gq (inactive) Reactome DB_ID: 9759685 1 Reactome DB_ID: 9777580 1 Reactome Database ID Release 78 9782866 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782866 Reactome R-MMU-428764 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428764.1 Reactome Database ID Release 78 9782868 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782868 Reactome R-MMU-428749 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428749.1 The TP receptor can activate Gq leading to stimulation of Phospholipase C and consequent increase in intracellular calcium. 1851174 Pubmed 1991 The G protein coupled to the thromboxane A2 receptor in human platelets is a member of the novel Gq family Shenker, A Goldsmith, P Unson, CG Spiegel, AM J Biol Chem 266:9309-13 inferred by electronic annotation IEA GO IEA Activated TP receptor binds G-protein G13 Activated TP receptor binds G-protein G13 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759644 1 Heterotrimeric G-protein G13 (inactive) [plasma membrane] Heterotrimeric G-protein G13 (inactive) Reactome DB_ID: 9759174 1 Reactome DB_ID: 427851 1 G-protein alpha (13):GDP [plasma membrane] G-protein alpha (13):GDP Reactome DB_ID: 114549 1 Reactome DB_ID: 427849 1 UniProt:P27601 Gna13 Gna13 Gna13 Gna-13 FUNCTION Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems (PubMed:21212405, PubMed:19151758, PubMed:16388592). Activates effector molecule RhoA by binding and activating RhoGEFs (ARHGEF1/p115RhoGEF, ARHGEF11/PDZ-RhoGEF and ARHGEF12/LARG) (PubMed:16388592). GNA13-dependent Rho signaling subsequently regulates transcription factor AP-1 (activating protein-1) (PubMed:19151758, PubMed:21212405). Promotes tumor cell invasion and metastasis by activating Rho/ROCK signaling pathway (By similarity). Inhibits CDH1-mediated cell adhesion in process independent from Rho activation (By similarity).SUBUNIT G proteins are composed of 3 units; alpha, beta and gamma (PubMed:16388592). The alpha chain contains the guanine nucleotide binding site (PubMed:16388592). Interacts with UBXD5 (By similarity). Interacts with HAX1 (By similarity). Interacts (in GTP-bound form) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane (By similarity). Interacts with RGS22 (By similarity). Interacts (in GTP-bound form) with ARHGEF1 (PubMed:16388592). Interacts (in GTP-bound form) with ARHGEF11 (via RGS domain) (PubMed:18940608). Interacts (in GTP-bound form) with ARHGEF12 (via RGS domain) (PubMed:16388592). Interacts with CTNND1 (PubMed:15240885). Interacts with GAS2L2 (PubMed:23994616).TISSUE SPECIFICITY Expressed in brain and testis, as well as in kidney and sperm (at protein level).PTM Phosphorylation on Thr-203 destabilizes the heterotrimer of alpha, beta and gamma, and inhibits Rho activation.SIMILARITY Belongs to the G-alpha family. G(12) subfamily. UniProt P27601 1 EQUAL 377 EQUAL Reactome Database ID Release 78 427851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427851 Reactome R-MMU-427851 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-427851.1 Reactome Database ID Release 78 9759644 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759644 Reactome R-MMU-398072 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-398072.1 Reactome DB_ID: 9777580 1 Reactome DB_ID: 9782894 1 TP receptor:Thromboxane A2:G-protein G13 (inactive) [plasma membrane] TP receptor:Thromboxane A2:G-protein G13 (inactive) Reactome DB_ID: 9759644 1 Reactome DB_ID: 9777580 1 Reactome Database ID Release 78 9782894 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782894 Reactome R-MMU-428905 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428905.1 Reactome Database ID Release 78 9782896 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782896 Reactome R-MMU-428909 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428909.1 The thromboxane receptor (TP) can activate G12 and G13. 16418336 Pubmed 2006 The G12 family of G proteins as a reporter of thromboxane A2 receptor activity Zhang, L DiLizio, C Kim, D Smyth, EM Manning, DR Mol Pharmacol 69:1433-40 16212421 Pubmed 2005 Coupling interaction between thromboxane A2 receptor and alpha-13 subunit of guanine nucleotide-binding protein Chou, KC J Proteome Res 4:1681-6 inferred by electronic annotation IEA GO IEA Gq activation by TP receptor Gq activation by TP 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> Reactome DB_ID: 9782866 1 Reactome DB_ID: 29438 1 Reactome DB_ID: 29420 1 Reactome DB_ID: 9782870 1 TP receptor:Thromboxane A2:G-protein Gq (active) [plasma membrane] TP receptor:Thromboxane A2:G-protein Gq (active) Reactome DB_ID: 9777580 1 Reactome DB_ID: 9759176 1 Reactome Database ID Release 78 9782870 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782870 Reactome R-MMU-428904 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428904.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9782866 Reactome Database ID Release 78 9782871 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782871 Reactome Database ID Release 78 9782873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782873 Reactome R-MMU-428750 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428750.1 The G-protein alpha subunit exchanges GDP for GTP inferred by electronic annotation IEA GO IEA G13 activation by TP receptor G13 activation by TP 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> Reactome DB_ID: 29438 1 Reactome DB_ID: 9782894 1 Reactome DB_ID: 29420 1 Reactome DB_ID: 9782898 1 TP receptor:Thromboxane A2:G-protein G13 (active) [plasma membrane] TP receptor:Thromboxane A2:G-protein G13 (active) Reactome DB_ID: 9777580 1 Reactome DB_ID: 9759654 1 Heterotrimeric G-protein G13 (active) [plasma membrane] Heterotrimeric G-protein G13 (active) Reactome DB_ID: 9759174 1 Reactome DB_ID: 9759615 1 G-protein alpha (13):GTP [plasma membrane] G-protein alpha (13):GTP Reactome DB_ID: 427849 1 1 EQUAL 377 EQUAL Reactome DB_ID: 29438 1 Reactome Database ID Release 78 9759615 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759615 Reactome R-MMU-398056 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-398056.1 Reactome Database ID Release 78 9759654 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759654 Reactome R-MMU-398074 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-398074.1 Reactome Database ID Release 78 9782898 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782898 Reactome R-MMU-428907 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428907.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9782894 Reactome Database ID Release 78 9782899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782899 Reactome Database ID Release 78 9782901 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782901 Reactome R-MMU-428917 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428917.1 The G-protein alpha subunit exchanges GDP for GTP inferred by electronic annotation IEA GO IEA Dissociation of the TP:Gq complex Dissociation of the TP:Gq 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> Reactome DB_ID: 9782870 1 Reactome DB_ID: 9758872 1 Reactome DB_ID: 391932 1 Reactome DB_ID: 9777578 1 1 EQUAL 343 EQUAL Reactome DB_ID: 9759174 1 Reactome Database ID Release 78 9782875 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782875 Reactome R-MMU-428752 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428752.1 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). inferred by electronic annotation IEA GO IEA Dissociation of the TP:G13 complex Dissociation of the TP:G13 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> Reactome DB_ID: 9782898 1 Reactome DB_ID: 391932 1 Reactome DB_ID: 9777578 1 1 EQUAL 343 EQUAL Reactome DB_ID: 9759174 1 Reactome DB_ID: 9759615 1 Reactome Database ID Release 78 9782903 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782903 Reactome R-MMU-428918 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428918.1 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861656 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861656 Reactome R-MMU-428930 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-428930.1 Thromboxane (TXA2) binds to the thromboxane receptor (TP). There are 2 splice variant forms of TP, differing in their cytoplasmic carboxyl terminal tails. TP beta was first identified in endothelial cells. TP alpha was identified in platelets and placenta. The major signalling route for TP is Gq-mediated stimulation of PLC and consequent increase in cellular calcium. TP also couples to G13, leading to stimulation of Rho and Rac. 14751539 Pubmed 2004 Cell signalling through thromboxane A2 receptors Huang, JS Ramamurthy, SK Lin, X Le Breton, GC Cell Signal 16:521-33 9780781749961 ISBN 2006 Hemostasis and Thrombosis: Basic Principles and Clinical Practice Colman, R Marder, V Clowes, A George, J Goldhaber, S Hemostasis and Thrombosis: Basic Principles and Clinical Practice (Book) 18374420 Pubmed 2008 Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology Nakahata, N Pharmacol Ther 118:18-35 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9861658 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9861658 Reactome R-MMU-392518 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392518.1 In the initial response to injury, platelets adhere to damaged blood vessels, responding to the exposure of collagen from the vascular epithelium. Once adhered they degranulate, releasing stored secondary agents such as ADP and ATP, and synthesized thromboxane A2. These amplify the response, activating and recruiting further platelets to the area and promoting platelet aggregation. Adenosine nucleotides secreted following platelet activation signal through P2 purinergic receptors on the platelet membrane. ADP activates P2Y1 and P2Y12 while ATP activates the ionotropic P2X1 receptor (Kunapuli et al. 2003). Activation of these receptors initiates a complex signaling cascade that ultimately results in platelet activation and thrombus formation (Kahner et al. 2006). ADP stimulation of P2Y1 and P2Y12 involves signaling via both the alpha and gamma:beta components of the heterotrimeric G-protein (Hirsch et al. 2001, 2006). 17059469 Pubmed 2006 Nucleotide receptor signaling in platelets Kahner, BN Shankar, H Murugappan, S Prasad, GL Kunapuli, SP J Thromb Haemost 4:2317-26 12681240 Pubmed 2003 Platelet purinergic receptors Kunapuli, SP Dorsam, RT Kim, S Quinton, TM Curr Opin Pharmacol 3:175-80 16543958 Pubmed 2006 Signaling through PI3Kgamma: a common platform for leukocyte, platelet and cardiovascular stress sensing Hirsch, E Lembo, G Montrucchio, G Rommel, C Costa, C Barberis, L Thromb Haemost 95:29-35 18077812 Pubmed 2007 Platelet activation and atherothrombosis Davì, G Patrono, C N Engl J Med 357:2482-94 11511514 Pubmed 2001 Resistance to thromboembolism in PI3Kgamma-deficient mice Hirsch, E Bosco, O Tropel, P Laffargue, M Calvez, R Altruda, F Wymann, M Montrucchio, G FASEB J 15:2019-21 inferred by electronic annotation IEA GO IEA Thrombin signalling through proteinase activated receptors (PARs) Thrombin signalling through proteinase activated receptors (PARs) 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> 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Activated thrombin (factor IIa) cleaves PAR3,4, activating them Activated thrombin (factor IIa) cleaves PAR3,4, activating them Thrombin-mediated activation of Proteinase-activated receptors This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9759914 1 PAR3, 4 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity F2rl2 [plasma membrane] F2rl3 [plasma membrane] UniProt O08675 UniProt O88634 Converted from EntitySet in Reactome Reactome DB_ID: 9759634 1 Thrombin-activated PARs [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity F2rl2 [plasma membrane] F2rl3 [plasma membrane] Converted from EntitySet in Reactome Reactome DB_ID: 9759920 1 PAR N-teminal fragments [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity F2rl3 [extracellular region] F2rl2 [extracellular region] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9759928 activated thrombin (factor IIa) [extracellular region] activated thrombin (factor IIa) Reactome DB_ID: 9759924 1 UniProt:P19221 F2 UniProt P19221 364 EQUAL 622 EQUAL Reactome DB_ID: 9759926 1 328 EQUAL 363 EQUAL Reactome DB_ID: 74112 6 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI 29108 Reactome Database ID Release 78 9759928 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759928 Reactome R-MMU-156786 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-156786.1 GO 0004252 GO molecular function Reactome Database ID Release 78 9759929 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759929 Reactome Database ID Release 78 9759931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759931 Reactome R-MMU-114697 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114697.1 Thrombin signaling is mediated at least in part by a small family of G protein-coupled Proteinase Activated Receptors (PARs). Human platelet activation by thrombin is mediated predominantly by PAR1; PAR4-induced platelet responses are less pronounced. PAR2 is not present in human platelets. PARs 1, 3 and 4 are activated when thrombin cleaves an N-terminal exodomain. This cleavage event unmasks a new N-terminus that serves as a tethered ligand that binds intramolecularly to the body of the receptor to effect transmembrane signaling. Intermolecular ligation of one PAR molecule by another can occur but, not surprisingly, appears to be less efficient than self-ligation. A synthetic peptide of sequence SFLLRN, the first six amino acids of the new N-terminus generated when thrombin cleaves PAR1, can activate PAR1 independent of protease and receptor cleavage. In addition to providing evidence for the tethered ligand mechanism, such tethered ligand-mimicking peptides have provided a convenient pharmacological tool for probing the effects of PAR activation in cells and tissues. 9087410 Pubmed 1997 Protease-activated receptor 3 is a second thrombin receptor in humans Ishihara, H Connolly, AJ Zeng, D Kahn, ML Zheng, YW Timmons, C Tram, T Coughlin, SR Nature 386:502-6 1672265 Pubmed 1991 Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation Vu, TK Hung, DT Wheaton, VI Coughlin, SR Cell 64:1057-68 9618465 Pubmed 1998 Cloning and characterization of human protease-activated receptor 4 Xu, WF Andersen, H Whitmore, TE Presnell, SR Yee, DP Ching, A Gilbert, T Davie, EW Foster, DC Proc Natl Acad Sci U S A 95:6642-6 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Activated thrombin (factor IIa) cleaves F2R (PAR1), activating it Activated thrombin (factor IIa) cleaves F2R (PAR1), activating it This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9859209 1 UniProt:P30558 F2r F2r Par1 F2r Cf2r FUNCTION High affinity receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis.DOMAIN The cleaved signal peptide may not be degraded and may function as an intracellular angiogenesis inhibitor peptide known as parstatin.PTM A proteolytic cleavage generates a new N-terminus that functions as a tethered ligand.PTM Phosphorylated in the C-terminal tail; probably mediating desensitization prior to the uncoupling and internalization of the receptor.SIMILARITY Belongs to the G-protein coupled receptor 1 family. UniProt P30558 22 EQUAL 425 EQUAL Reactome DB_ID: 9781098 1 42 EQUAL 425 EQUAL Reactome DB_ID: 9859211 1 27 EQUAL 41 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9759928 Reactome Database ID Release 78 9859213 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9859213 Reactome R-MMU-9708859 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-9708859.1 Thrombin activates proteinase activated receptors (PARs) that signal through heterotrimeric G proteins of the G12/13 and Gq families. In human platelets, PAR1 (F2R) is the predominant thrombin receptor (Vu et al. 1991). Gq is necessary for platelet secretion and aggregation in response to thrombin but is not necessary for thrombin-triggered shape change. G13 appears to contribute to platelet aggregation as well as shape change in response to low concentrations of thrombin but to be unnecessary at higher agonist concentrations; G12 appears to be dispensable for thrombin signaling in platelets.<br><br>The proprotein form of F2R is activated when thrombin cleaves the N-terminal exodomain. This cleavage event unmasks a new N-terminus that serves as a tethered ligand that binds intramolecularly to the body of the receptor to effect transmembrane signaling (Vu et al. 1991). Intermolecular ligation of one PAR molecule by another can occur but, not surprisingly, appears to be less efficient than self-ligation. A synthetic peptide of sequence SFLLRN, the first six amino acids of the new N-terminus generated when thrombin cleaves PAR1, can activate PAR1 independent of protease and receptor cleavage. In addition to providing evidence for the tethered ligand mechanism, such tethered ligand-mimicking peptides have provided a convenient pharmacological tool for probing the effects of PAR activation in cells and tissues. inferred by electronic annotation IEA GO IEA Thrombin-activated PARs binds G-protein Gq Thrombin-activated PARs binds G-protein Gq 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 Reactome DB_ID: 9759634 1 Reactome DB_ID: 9759685 1 Reactome DB_ID: 9759687 1 Thrombin-activated PARs:Gq (inactive) [plasma membrane] Thrombin-activated PARs:Gq (inactive) Converted from EntitySet in Reactome Reactome DB_ID: 9759634 1 Reactome DB_ID: 9759685 1 Reactome Database ID Release 78 9759687 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759687 Reactome R-MMU-397803 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-397803.1 Reactome Database ID Release 78 9780482 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780482 Reactome R-MMU-396996 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-396996.1 Thrombin signalling through PARs is mediated in part through the Gq family of G-proteins. Gq knockout mice have defective platelet responses to thrombin (as well as to ADP and thromboxane). 9296496 Pubmed 1997 Defective platelet activation in G alpha(q)-deficient mice Offermanns, S Toombs, CF Hu, YH Simon, MI Nature 389:183-6 8982657 Pubmed 1996 Direct evidence for two distinct G proteins coupling with thrombin receptors in human neuroblastoma SH-EP cells Ogino, Y Tanaka, K Shimizu, N Eur J Pharmacol 316:105-9 inferred by electronic annotation IEA GO IEA Thrombin-activated PARs activate Gq Thrombin-activated PARs activate Gq Gq activation by PAR This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759687 1 Reactome DB_ID: 29438 1 Reactome DB_ID: 29420 1 Reactome DB_ID: 9759689 1 Thrombin-activated PAR:Gq (active) [plasma membrane] Thrombin-activated PAR:Gq (active) Converted from EntitySet in Reactome Reactome DB_ID: 9759634 1 Reactome DB_ID: 9759176 1 Reactome Database ID Release 78 9759689 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759689 Reactome R-MMU-397802 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-397802.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9759634 GO 0004930 GO molecular function Reactome Database ID Release 78 9759659 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759659 Reactome Database ID Release 78 9759691 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759691 Reactome R-MMU-114558 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114558.1 Activated PAR stimulates the G alpha (q) subunit to release GDP and bind GTP (which is present in much greater concentrations physiologically). This activation is required for Gq to participate in downstream signalling events. 16102047 Pubmed 2005 Protease-activated receptors in hemostasis, thrombosis and vascular biology Coughlin, SR J Thromb Haemost 3:1800-14 inferred by electronic annotation IEA GO IEA Thrombin-activated PARs:Gq (active) dissociate Thrombin-activated PARs:Gq (active) dissociate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759689 1 Reactome DB_ID: 9758872 1 Converted from EntitySet in Reactome Reactome DB_ID: 9759634 1 Reactome DB_ID: 9759174 1 Reactome Database ID Release 78 9780484 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780484 Reactome R-MMU-397835 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-397835.1 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). inferred by electronic annotation IEA GO IEA Thrombin-activated PARs activate G12/13 Thrombin-activated PARs activate G12/13 G12/13 activation by PAR This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759648 1 Thrombin activated PAR:G12/13 (inactive) [plasma membrane] Thrombin activated PAR:G12/13 (inactive) Converted from EntitySet in Reactome Reactome DB_ID: 9759634 1 Converted from EntitySet in Reactome Reactome DB_ID: 9759646 1 G-protein G12/G13 (inactive) [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 78 9759648 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759648 Reactome R-MMU-397883 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-397883.1 Reactome DB_ID: 29438 1 Reactome DB_ID: 9759658 1 Thrombin activated PAR:G12/13 (active) [plasma membrane] Thrombin activated PAR:G12/13 (active) Converted from EntitySet in Reactome Reactome DB_ID: 9759634 1 Converted from EntitySet in Reactome Reactome DB_ID: 9759656 1 G-protein G12/G13 (active) [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 78 9759658 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759658 Reactome R-MMU-397884 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-397884.1 Reactome DB_ID: 29420 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9759634 Reactome Database ID Release 78 9759661 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759661 Reactome R-MMU-114552 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114552.1 PAR1, 3 and 4 have been shown to directly couple with G12/13 (Offermanns et al. 1994). G12 and G13 have overlapping but distinct signalling roles (Suzuki et al. 2009). Evidence from conditional knockout mice (KOs) suggests that G13 is the subtype responsible for platelet shape change and aggregation responses in response to low and intermediate concentrations of thrombin, thromboxane and collagen. Platelets from G12 KOs were indistinguishable from wild-type, while those from mice with disrupted G13 had impaired shape change and aggregation responses, failed to form stable thrombi ex vivo, and exhibited a large increase in tailbleeding times (Moers et al. 2003). Both subtypes of G12/13 are unnecessary for platelet shape change and aggregation at higher agonist concentrations. The alpha-subunits of G12 and 13 bind RhoGEFs (guanine nucleotide exchange factors, which activate small G proteins) providing a path to Rho-mediated cytoskeletal responses that are involved in shape change in platelets and permeability and migration in endothelial cells.<br> 19212140 Pubmed 2009 Regulation and physiological functions of G12/13-mediated signaling pathways Suzuki, N Hajicek, N Kozasa, T Neurosignals 17:55-70 14528298 Pubmed 2003 G13 is an essential mediator of platelet activation in hemostasis and thrombosis Moers, A Nieswandt, B Massberg, S Wettschureck, N Grüner, S Konrad, I Schulte, V Aktas, B Gratacap, MP Simon, MI Gawaz, M Offermanns, S Nat Med 9:1418-22 8290554 Pubmed 1994 G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets Offermanns, S Laugwitz, KL Spicher, K Schultz, G Proc Natl Acad Sci U S A 91:504-8 inferred by electronic annotation IEA GO IEA Thrombin-activated PARs:G12/13 (active) dissociate Thrombin-activated PARs:G12/13 (active) dissociate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759658 1 Converted from EntitySet in Reactome Reactome DB_ID: 9759634 1 Reactome DB_ID: 9759174 2 Converted from EntitySet in Reactome Reactome DB_ID: 9780486 1 G-protein alpha (12/13):GTP [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 78 9780488 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780488 Reactome R-MMU-397891 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-397891.1 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). inferred by electronic annotation IEA GO IEA F2R binds ARRB1 F2R binds ARRB1 Activated PAR1 binds Beta-arrestin-1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9781098 1 42 EQUAL 425 EQUAL Reactome DB_ID: 5632461 1 UniProt:Q8BWG8 Arrb1 Arrb1 Arrb1 FUNCTION Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Involved in IL8-mediated granule release in neutrophils. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Required for atypical chemokine receptor ACKR2-induced RAC1-LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. Involved in the internalization of the atypical chemokine receptor ACKR3 (By similarity). Negatively regulates the NOTCH signaling pathway by mediating the ubiquitination and degradation of NOTCH1 by ITCH. Participates in the recruitment of the ubiquitin-protein ligase to the receptor (PubMed:23886940).SUBUNIT Monomer. Homodimer. Homooligomer; the self-association is mediated by InsP6-binding. Heterooligomer with ARRB2; the association is mediated by InsP6-binding. Interacts with ADRB2 (phosphorylated). Interacts with CHRM2 (phosphorylated). Interacts with LHCGR. Interacts with CYTH2 and CASR. Interacts with AP2B1 (dephosphorylated); phosphorylation of AP2B1 disrupts the interaction. Interacts (dephosphorylated at Ser-412) with CLTC. Interacts with CCR2 and GRK2. Interacts with CRR5. Interacts with PTAFR (phosphorylated on serine residues). Interacts with CLTC and MAP2K3. Interacts with CREB1. Interacts with TRAF6. Interacts with IGF1R and MDM2. Interacts with C5AR1. Interacts with PDE4D. Interacts with SRC (via the SH3 domain and the protein kinase domain); the interaction is independent of the phosphorylation state of SRC C-terminus. Interacts with TACR1. Interacts with RAF1. Interacts with DVL1; the interaction is enhanced by phosphorylation of DVL1. Interacts with DVL2; the interaction is enhanced by phosphorylation of DVL2. Interacts with IGF1R. Interacts with CHUK, IKBKB and MAP3K14. Associates with MAP kinase p38. Part of a MAPK signaling complex consisting of TACR1, ARRB1, SRC, MAPK1 (activated) and MAPK3 (activated). Part of a MAPK signaling complex consisting of F2RL1, ARRB1, RAF1, MAPK1 (activated) and MAPK3 (activated). Interacts with GPR143 (By similarity). Interacts with MAP2K4/MKK4. Interacts with HCK and CXCR1 (phosphorylated) (By similarity). Interacts with ACKR3 and ACKR4 (By similarity). Interacts with ARRDC1; the interaction is direct (PubMed:23886940). Interacts with GPR61, GPR62 and GPR135 (By similarity).DOMAIN The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1. Binding to phosphorylated GPCRs induces a conformationanl change that exposes the motif to the surface (By similarity).DOMAIN The N-terminus binds InsP6 with low affinity.DOMAIN The C-terminus binds InsP6 with high affinity.PTM Constitutively phosphorylated at in the cytoplasm. At the plasma membrane, is rapidly dephosphorylated, a process that is required for clathrin binding and ADRB2 endocytosis but not for ADRB2 binding and desensitization. Once internalized, is rephosphorylated (By similarity).PTM The ubiquitination status appears to regulate the formation and trafficking of beta-arrestin-GPCR complexes and signaling. Ubiquitination appears to occur GPCR-specific. Ubiquitinated by MDM2; the ubiquitination is required for rapid internalization of ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a dissociation of the beta-arrestin-GPCR complex. Stimulation of a class A GPCR, such as ADRB2, induces transient ubiquitination and subsequently promotes association with USP33 (By similarity).SIMILARITY Belongs to the arrestin family. UniProt Q8BWG8 1 EQUAL 418 EQUAL Reactome DB_ID: 9781101 1 F2R:ARRB1 [plasma membrane] F2R:ARRB1 Reactome DB_ID: 9781098 1 42 EQUAL 425 EQUAL Reactome DB_ID: 5632461 1 1 EQUAL 418 EQUAL Reactome Database ID Release 78 9781101 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781101 Reactome R-MMU-418080 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418080.1 Reactome Database ID Release 78 9781103 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781103 Reactome R-MMU-418091 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418091.1 Following receptor activation, PAR1 complexes with beta-arrestin. Beta-arrestins are adaptor proteins that play a central role in GPCR desensitization and internalization, and also act as scaffolds for the formation of signalling complexes that are independent of G-protein signalling. 16580177 Pubmed 2006 Opposing effects of beta-arrestin1 and beta-arrestin2 on activation and degradation of Src induced by protease-activated receptor 1 Kuo, FT Lu, TL Fu, HW Cell Signal 18:1914-23 17305471 Pubmed 2007 Beta-arrestins and cell signaling DeWire, SM Ahn, S Lefkowitz, RJ Shenoy, SK Annu Rev Physiol 69:483-510 inferred by electronic annotation IEA GO IEA F2R binds ARRB2 F2R binds ARRB2 Activated PAR1 binds beta-arrestin-2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9781121 1 UniProt:Q91YI4 Arrb2 Arrb2 Arrb2 FUNCTION Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Mediates endocytosis of CCR7 following ligation of CCL19 but not CCL21. Involved in internalization of P2RY1, P2RY4, P2RY6 and P2RY11 and ATP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 and subsequent recycling or degradation. Involved in ubiquitination of IGF1R. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Acts as signaling scaffold for the AKT1 pathway. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Increases ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Involved in CCR7-mediated ERK1/2 signaling involving ligand CCL19. Is involved in type-1A angiotensin II receptor/AGTR1-mediated ERK activity. Is involved in type-1A angiotensin II receptor/AGTR1-mediated MAPK10 activity. Is involved in dopamine-stimulated AKT1 activity in the striatum by disrupting the association of AKT1 with its negative regulator PP2A. Involved in AGTR1-mediated chemotaxis. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. Suppresses UV-induced NF-kappa-B-dependent activation by interacting with CHUK. The function is promoted by stimulation of ADRB2 and dephosphorylation of ARRB2. Involved in IL8-mediated granule release in neutrophils (By similarity). Involved in p53/TP53-mediated apoptosis by regulating MDM2 and reducing the MDM2-mediated degradation of p53/TP53. May serve as nuclear messenger for GPCRs. Upon stimulation of OR1D2, may be involved in regulation of gene expression during the early processes of fertilization. Also involved in regulation of receptors other than GPCRs. Involved in endocytosis of TGFBR2 and TGFBR3 and down-regulates TGF-beta signaling such as NF-kappa-B activation. Involved in endocytosis of low-density lipoprotein receptor/LDLR. Involved in endocytosis of smoothened homolog/Smo, which also requires GRK2. Involved in endocytosis of SLC9A5. Involved in endocytosis of ENG and subsequent TGF-beta-mediated ERK activation and migration of epithelial cells. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Involved in insulin resistance by acting as insulin-induced signaling scaffold for SRC, AKT1 and INSR. Involved in regulation of inhibitory signaling of natural killer cells by recruiting PTPN6 and PTPN11 to KIR2DL1. Involved in the internalization of the atypical chemokine receptor ACKR3 (By similarity). Acts as an adapter protein coupling FFAR4 receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis. During the activation step of NLRP3 inflammasome, directly associates with NLRP3 leading to inhibition of proinflammatory cytokine release and inhibition of inflammation.SUBUNIT Homooligomer; the self-association is mediated by InsP6-binding (Probable). Heterooligomer with ARRB1; the association is mediated by InsP6-binding. Interacts with ADRB2 AND CHRM2. Interacts with PDE4A. Interacts with PDE4D. Interacts with MAPK10, MAPK1 and MAPK3. Interacts with DRD2. Interacts with FSHR. Interacts with CLTC. Interacts with HTR2C. Interacts with CCR5. Interacts with CXCR4. Interacts with SRC. Interacts with DUSP16; the interaction is interrupted by stimulation of AGTR1 and activation of MAPK10. Interacts with CHUK; the interaction is enhanced stimulation of ADRB2. Interacts with RELA. Interacts with MDM2; the interaction is enhanced by activation of GPCRs. Interacts with SLC9A5. Interacts with TRAF6. Interacts with IGF1R. Interacts with ENG. Interacts with ARRB2. Interacts with KIR2DL1, KIR2DL3 and KIR2DL4. Interacts with LDLR. Interacts with AP2B1. Interacts with C5AR1. Interacts with RAF1. Interacts with MAP2K1. Interacts with MAPK1. Interacts with MAPK10; the interaction enhances MAPK10 activation by MAP3K5. Interacts with MAP2K4; the interaction is enhanced by presence of MAP3K5 and MAPK10. Interacts with MAP3K5. Interacts with AKT1. Interacts with IKBKB and MAP3K14. Interacts with SMO (activated). Interacts with GSK3A and GSK3B. Interacts with CXCR4; the interaction is dependent on C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with GPR143. Interacts with HCK and CXCR1 (phosphorylated) (By similarity). Associates with protein phosphatase 2A (PP2A). Interacts with ACKR3 and ACKR4 (By similarity). Interacts with ARRDC1; the interaction is direct (By similarity). Interacts with GPR61, GPR62 and GPR135 (By similarity). Interacts (via NACHT and LRR domains) with NLRP3; this interaction is direct and inducible by omega-3 polyunsaturated fatty acids (PUFAs) (By similarity). Interacts with FFAR4 (via C-terminus); this interaction is stimulated by long-chain fatty acids (LCFAs) (PubMed:26873857).TISSUE SPECIFICITY Predominantly localized in neuronal tissues and in the spleen.PTM Phosphorylated at Thr-383 in the cytoplasm; probably dephosphorylated at the plasma membrane. The phosphorylation does not regulate internalization and recycling of ADRB2, interaction with clathrin or AP2B1 (By similarity).PTM The ubiquitination status appears to regulate the formation and trafficking of beta-arrestin-GPCR complexes and signaling. Ubiquitination appears to occur GPCR-specific. Ubiquitinated by MDM2; the ubiquitination is required for rapid internalization of ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a dissociation of the beta-arrestin-GPCR complex. Stimulation of a class A GPCR, such as ADRB2, induces transient ubiquitination and subsequently promotes association with USP33. Stimulation of a class B GPCR promotes a sustained ubiquitination (By similarity).PTM Hydroxylation by PHD2 modulates the rate of internalization by slowing down recruitment to the plasma membrane and inhibiting subsequent co-internalization with class A receptors.DISRUPTION PHENOTYPE Loss of beta-2 adrenergic receptor/ADRB2 ubiquitination. Reduction of dopamine-dependent behaviors, loss of Akt1 regulation by dopamine in the striatum and disruption of the dopamine-dependent interaction of Akt1 with its negative regulator, protein phosphatase 2A. Increased serum LDL-cholesterol levels upon high fat diet. Exacerbates insulin resistance. Elevated cytotoxicity of natural killer cells and lowered susceptibility to mouse cytomegalovirus infection.SIMILARITY Belongs to the arrestin family. UniProt Q91YI4 1 EQUAL 409 EQUAL Reactome DB_ID: 9781098 1 42 EQUAL 425 EQUAL Reactome DB_ID: 9781123 1 F2R:ARRB2 [plasma membrane] F2R:ARRB2 Reactome DB_ID: 9781121 1 1 EQUAL 409 EQUAL Reactome DB_ID: 9781098 1 42 EQUAL 425 EQUAL Reactome Database ID Release 78 9781123 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781123 Reactome R-MMU-418167 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418167.1 Reactome Database ID Release 78 9781125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781125 Reactome R-MMU-418172 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418172.1 Following receptor activation, PAR1 complexes with beta-arrestin. Beta-arrestins are adaptor proteins that play a central role in GPCR desensitization and internalization, and also act as scaffolds for the formation of signalling complexes that are independent of G-protein signalling. inferred by electronic annotation IEA GO IEA F2R:ARRB1 binds MAPKs, SRC-1 F2R:ARRB1 binds MAPKs, SRC-1 Beta-arrestin-1 acts as scaffold for a PAR1 signalling 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> Reactome DB_ID: 9767647 1 2 EQUAL 536 EQUAL Reactome DB_ID: 9781101 1 Converted from EntitySet in Reactome Reactome DB_ID: 9781105 1 MAPKs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Mapk1 [cytosol] Mapk3 [cytosol] UniProt P63085 UniProt Q63844 Reactome DB_ID: 9781107 1 F2R:ARRB1:MAPKs:SRC-1 [plasma membrane] F2R:ARRB1:MAPKs:SRC-1 Reactome DB_ID: 9767647 1 2 EQUAL 536 EQUAL Reactome DB_ID: 9781101 1 Converted from EntitySet in Reactome Reactome DB_ID: 9781105 1 Reactome Database ID Release 78 9781107 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781107 Reactome R-MMU-418103 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418103.1 Reactome Database ID Release 78 9781118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781118 Reactome R-MMU-418170 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418170.1 Beta-arrestins can serve as scaffolding molecules that facilitate G-protein independent cell signaling 9924018 Pubmed 1999 Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes Luttrell, LM Ferguson, SS Daaka, Y Miller, WE Maudsley, S Della Rocca, GJ Lin, F Kawakatsu, H Owada, K Luttrell, DK Caron, Marc G Lefkowitz, RJ Science 283:655-61 inferred by electronic annotation IEA GO IEA F2R:ARRB2 binds MAPKs, SRC-1 F2R:ARRB2 binds MAPKs, SRC-1 Beta-arrestin-2 acts as scaffold for a PAR1 signalling 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> Reactome DB_ID: 9781123 1 Reactome DB_ID: 9767647 1 2 EQUAL 536 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9781105 1 Reactome DB_ID: 9781127 1 F2R:ARRB2:MAPKs:SRC-1 [plasma membrane] F2R:ARRB2:MAPKs:SRC-1 Reactome DB_ID: 9781123 1 Reactome DB_ID: 9767647 1 2 EQUAL 536 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9781105 1 Reactome Database ID Release 78 9781127 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781127 Reactome R-MMU-418179 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418179.1 Reactome Database ID Release 78 9781129 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781129 Reactome R-MMU-418176 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418176.1 Beta-arrestins can serve as scaffolding molecules that facilitate G-protein independent cell signaling inferred by electronic annotation IEA GO IEA SRC-1 is activated (in F2R:ARRB1:MAPKs:SRC-1) SRC-1 is activated (in F2R:ARRB1:MAPKs:SRC-1) Activation of beta-arrestin-1-bound Src 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> Reactome DB_ID: 9781107 1 Reactome DB_ID: 9781107 1 Reactome Database ID Release 78 9781109 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781109 Reactome R-MMU-418158 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418158.1 The activity of Src-kinase is increased when bound to Beta-arrestin-1. The mechanism for this activation is not clear. Src bound to beta -arrestin 1 is substantially dephosphorylated at Tyr530 and this is often associated with Src activation. Binding results with Y530F mutants of Src suggest that binding of Src to arrestin causes a conformational activation of the kinase, rather than a change in phosphorylation. However, increased phosphorylation of Src Tyr419 in cells overexpressing beta-arrestin-1 has been reported to correlate with PAR1 activation, beta-arrestin signalling complex formation, and increased ERK activation. inferred by electronic annotation IEA GO IEA SRC-1 bound to ARRB2 is not activated SRC-1 bound to ARRB2 is not activated Src bound to beta-arrestin-2 is not 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> Reactome DB_ID: 9781127 1 Reactome DB_ID: 9781127 1 Reactome Database ID Release 78 9781131 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781131 Reactome R-MMU-418200 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418200.1 Activated PAR1 can induce the formation of signalling complexes with a beta-arrestin scaffold. When beta-arrestin-1 is incorporated this leads to Src and subsequent ERK activation. In contrast, complexes containing beta-arrestin-2 do not lead to Src and ERK activation. inferred by electronic annotation IEA GO IEA 2.7.10 Activated SRC-1 activates MAPKs (in F2R:ARRB1:MAPKs:active SRC-1) Activated SRC-1 activates MAPKs (in F2R:ARRB1:MAPKs:active SRC-1) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9781107 1 Reactome DB_ID: 9781113 1 F2R:ARRB1:active MAPKs:active SRC-1 [plasma membrane] F2R:ARRB1:active MAPKs:active SRC-1 Reactome DB_ID: 9767647 1 2 EQUAL 536 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9781111 1 p-T,Y MAPKs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Mapk3 [cytosol] phospho-Mapk1 [cytosol] Reactome DB_ID: 9781101 1 Reactome Database ID Release 78 9781113 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781113 Reactome R-MMU-418210 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418210.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9781107 GO 0004713 GO molecular function Reactome Database ID Release 78 9781114 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781114 Reactome Database ID Release 78 9781116 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781116 Reactome R-MMU-418163 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-418163.1 Within the beta-arrestin-1:Src:ERK complex, activated Src phosphorylates and activates ERK. ERK activation requires dual Thr and Tyr phosphorylations, at Thr202/Tyr204 for human ERK1 and Thr185/Tyr187 for human ERK2. Significant ERK activation requires phosphorylation at both sites, with Tyr phosphorylation preceding that of Thr. This reaction is given as a black-box event because the phosphorylation state of ERK on binding to beta-arrestin-1 is unknown. 9228083 Pubmed 1997 Mechanistic studies of the dual phosphorylation of mitogen-activated protein kinase Ferrell JE, Jr Bhatt, RR J Biol Chem 272:19008-16 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9860558 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9860558 Reactome R-MMU-456926 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-456926.1 Thrombin activates proteinase activated receptors (PARs) that signal through heterotrimeric G proteins of the G12/13 and Gq families, thereby connecting to a host of intracellular signaling pathways. Thrombin activates PARs by cleaving an N-terminal peptide that then binds to the body of the receptor to effect transmembrane signaling. Intermolecular ligation of one PAR molecule by another can occur but is less efficient than self-ligation. A synthetic peptide of sequence SFLLRN, the first six amino acids of the new N-terminus generated when thrombin cleaves PAR1, can activate PAR1 independent of protease and receptor cleavage. PARs are key to platelet activation. Four PARs have been identified, of which PARs 1 ,3 and 4 are substrates for thrombin. In humans PAR 1 is the predominant thrombin receptor followed by PAR4 which is less responsive to thrombin. PAR 3 is not considered important for human platelet responses as it is minimally expressed, though this is not the case for mouse. PAR2 is not expressed in platelets. In mouse platelets, Gq is necessary for platelet secretion and aggregation in response to thrombin but is not necessary for thrombin-triggered shape change. G13 appears to contribute to platelet aggregation as well as shape change in response to low concentrations of thrombin but to be unnecessary at higher agonist concentrations; G12 appears to be dispensable for thrombin signaling in platelets. G alpha (q) activates phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinase cassettes and other proteins that mediate cellular responses ranging from granule secretion, integrin activation, and aggregation in platelets. Gbeta:gamma subunits can activate phosphoinositide-3 kinase and other lipid modifying enzymes, protein kinases, and channels. PAR1 activation indirectly leads to activation of cell surface 'sheddases' that liberate ligands for receptor tyrosine kinases, providing a link between thrombin and receptor tyrosine kinases involved in cell growth and differentiation. The pleiotrophic effects of PAR activation are consistent with many of thrombin's diverse actions on cells. 11001069 Pubmed 2000 Thrombin signalling and protease-activated receptors Coughlin, SR Nature 407:258-64 inferred by electronic annotation IEA GO IEA GPVI-mediated activation cascade GPVI-mediated activation cascade This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.10 Fyn/Lyn-mediated phosphorylation of FcR1 gamma Fyn/Lyn-mediated phosphorylation of FcR1 gamma This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9759811 1 GPVI:FceRI gamma:FYN:LYN:Collagen type I [plasma membrane] GPVI:FceRI gamma:FYN:LYN:Collagen type I Reactome DB_ID: 9759796 1 Reactome DB_ID: 9759809 1 GPVI:FceRI gamma:FYN:LYN [plasma membrane] GPVI:FceRI gamma:FYN:LYN Reactome DB_ID: 420333 1 UniProt:P39688 Fyn 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 DB_ID: 1112642 1 UniProt:P25911 Lyn 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 DB_ID: 9759805 1 GP VI : FceRI gamma dimer [plasma membrane] GP VI : FceRI gamma dimer Reactome DB_ID: 9759800 1 UniProt:P0C191 Gp6 UniProt P0C191 21 EQUAL 339 EQUAL Reactome DB_ID: 9759803 1 FCERIG dimer [plasma membrane] FCERIG dimer Reactome DB_ID: 5621125 2 UniProt:P20491 Fcer1g Fcer1g Fcer1g Fce1g FUNCTION Adapter protein containing an immunoreceptor tyrosine-based activation motif (ITAM) that transduces activation signals from various immunoreceptors. As a component of the high-affinity immunoglobulin E (IgE) receptor, mediates allergic inflammatory signaling in mast cells (PubMed:14764707). As a constitutive component of interleukin-3 receptor complex, selectively mediates interleukin 4/IL4 production by basophils, priming T-cells toward effector T-helper 2 subset (PubMed:19098920). Associates with pattern recognition receptors CLEC4D and CLEC4E to form a functional signaling complex in myeloid cells. Binding of mycobacterial trehalose 6,6'-dimycolate (TDM) to this receptor complex leads to phosphorylation of ITAM, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes (PubMed:23602766) (Probable). May function cooperatively with other activating receptors. Functionally linked to integrin beta-2/ITGB2-mediated neutrophil activation (PubMed:17086186). Also involved in integrin alpha-2/ITGA2-mediated platelet activation (PubMed:9171347).SUBUNIT IgE Fc receptor is a tetramer of an alpha chain, a beta chain, and two disulfide linked gamma chains. Associates with FCGR1A; forms a functional signaling complex (By similarity). Associates with CLEC6A (PubMed:17050534). Interacts with CLEC4E (PubMed:23602766, PubMed:18776906). Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK, enabling integrin-mediated activation of neutrophils and macrophages (PubMed:17086186). Interacts with CSF2RB and recruits SYK in response to IL3 stimulation; this interaction is direct (PubMed:19098920). Interacts with CD300LH; the interaction may be indirect (PubMed:20817736). Interacts with CD300LD (PubMed:20817736). Interacts with TARM1 (By similarity).TISSUE SPECIFICITY Expressed in mast cells (at protein level) (PubMed:14764707). Expressed in basophils (at protein level) (PubMed:19098920).DISRUPTION PHENOTYPE Knockout mice are resistant to IgE-mediated systemic anaphylaxis.SIMILARITY Belongs to the CD3Z/FCER1G family. UniProt P20491 19 EQUAL 86 EQUAL Reactome Database ID Release 78 9759803 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759803 Reactome R-MMU-210223 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-210223.1 Reactome Database ID Release 78 9759805 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759805 Reactome R-MMU-114575 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114575.1 Reactome Database ID Release 78 9759809 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759809 Reactome R-MMU-432297 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-432297.1 Reactome Database ID Release 78 9759811 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759811 Reactome R-MMU-434812 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-434812.1 Reactome DB_ID: 29370 2 Reactome DB_ID: 9759823 1 GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN:Collagen type I [plasma membrane] GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN:Collagen type I Reactome DB_ID: 9759796 1 Reactome DB_ID: 9759821 1 GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN [plasma membrane] GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN Reactome DB_ID: 9759819 1 GP VI : phosphorylated Fc Epsilon R1 gamma complex [plasma membrane] GP VI : phosphorylated Fc Epsilon R1 gamma complex Reactome DB_ID: 9759817 2 O4'-phospho-L-tyrosine at 65 (in Homo sapiens) 65 EQUAL O4'-phospho-L-tyrosine at 76 (in Homo sapiens) 76 EQUAL 19 EQUAL 86 EQUAL Reactome DB_ID: 9759800 1 21 EQUAL 339 EQUAL Reactome Database ID Release 78 9759819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759819 Reactome R-MMU-114598 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114598.1 Reactome DB_ID: 420333 1 2 EQUAL 537 EQUAL Reactome DB_ID: 1112642 1 2 EQUAL 512 EQUAL Reactome Database ID Release 78 9759821 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759821 Reactome R-MMU-434820 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-434820.1 Reactome Database ID Release 78 9759823 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759823 Reactome R-MMU-434822 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-434822.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9759811 Reactome Database ID Release 78 9759824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759824 Reactome Database ID Release 78 9759826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759826 Reactome R-MMU-114600 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114600.1 At the beginning of this reaction, 1 molecule of 'GP VI:Fc Epsilon R1 gamma:Collagen IV complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'GP VI:phosphorylated Fc Epsilon R1 gamma:Collagen IV complex' are present.<br><br> This reaction is mediated by the 'protein-tyrosine kinase activity' of 'GP VI: Fc Epsilon R1 gamma: Collagen IV: SRC'.<br> 9028946 Pubmed 1997 A collagen-like peptide stimulates tyrosine phosphorylation of syk and phospholipase C gamma2 in platelets independent of the integrin alpha2beta1 Asselin, J Gibbins, JM Achison, M Lee, YH Morton, LF Farndale, RW Barnes, MJ Watson, SP Blood 89:1235-42 inferred by electronic annotation IEA GO IEA Binding of Syk tyrosine kinase Binding of Syk tyrosine 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> Reactome DB_ID: 9759903 1 UniProt:P48025 Syk Syk ptk72 Syk 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. 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 plays also 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. Plays also 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 DB_ID: 9759823 1 Reactome DB_ID: 9759933 1 GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN:Collagen type I:SYK [plasma membrane] GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN:Collagen type I:SYK Reactome DB_ID: 9759903 1 1 EQUAL 635 EQUAL Reactome DB_ID: 9759823 1 Reactome Database ID Release 78 9759933 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759933 Reactome R-MMU-434911 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-434911.1 Reactome Database ID Release 78 9759935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759935 Reactome R-MMU-139842 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-139842.1 Syk binds to the phosphorylated ITAM motif of Fc epsilon R1 gamma chain, each SH2 domain binding a phosphorylated tyrosine. Unlike Zap70, Syk appears to autophosphorylate, so does not require Src family kinases for activation. 10669724 Pubmed 2000 Regulatory and signaling properties of the Vav family Bustelo, XR Mol Cell Biol 20:1461-77 inferred by electronic annotation IEA GO IEA 2.7.10.2 SYK autophosphorylates SYK autophosphorylates This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759933 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9786006 1 GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN:Collagen type I:p-Y348-SYK [plasma membrane] GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN:Collagen type I:p-Y348-SYK Reactome DB_ID: 9782977 1 O4'-phospho-L-tyrosine at 348 348 EQUAL 1 EQUAL 635 EQUAL Reactome DB_ID: 9759823 1 Reactome Database ID Release 78 9786006 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9786006 Reactome R-MMU-453171 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-453171.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9759933 GO 0004715 GO molecular function Reactome Database ID Release 78 9786009 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9786009 Reactome Database ID Release 78 9786017 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9786017 Reactome R-MMU-453200 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-453200.1 Binding of Syk causes conformational changes that lead to Syk activation by autophosphorylation. Syk can be activated by a number of phosphorylation events, and it has been proposed that Syk may function as a switch whereby any of several possible stimuli trigger the acquisition of similar activated conformations. (Tsang et al. 2008). These phosphorylations both modulate Syk's catalytic activity (Keshvara et al. 1997) and generate docking sites for SH2 domain-containing proteins, such as c-Cbl, PLC, and Vav1. Syk tyrosine phosphorylation is reduced in the presence of the ITIM-containing immunoglobulin superfamily transmembrane protein G6B (Mori et al. 2008). 1874735 Pubmed 1991 Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis Taniguchi, T Kobayashi, T Kondo, J Takahashi, K Nakamura, H Suzuki, J Nagai, K Yamada, T Nakamura, S Yamamura, H J Biol Chem 266:15790-6 18818202 Pubmed 2008 Molecular mechanism of the Syk activation switch Tsang, E Giannetti, AM Shaw, D Dinh, M Tse, JK Gandhi, S Ho, H Wang, S Papp, E Bradshaw, JM J Biol Chem 283:32650-9 18955485 Pubmed 2008 G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2 Mori, Jun Pearce, Andrew C Spalton, Jennifer C Grygielska, Beata Eble, Johannes A Tomlinson, Michael G Senis, Yotis A Watson, Steve P J. Biol. Chem. 283:35419-27 19409513 Pubmed 2009 Conformational rearrangements upon Syk auto-phosphorylation Arias-Palomo, E Recuero-Checa, MA Bustelo, XR Llorca, O Biochim Biophys Acta 1794:1211-7 9099676 Pubmed 1997 Syk activation and dissociation from the B-cell antigen receptor is mediated by phosphorylation of tyrosine 130 Keshvara, LM Isaacson, C Harrison, ML Geahlen, RL J Biol Chem 272:10377-81 11481033 Pubmed 2001 Structure and function of Syk protein-tyrosine kinase Sada, K Takano, T Yanagi, S Yamamura, H J Biochem 130:177-86 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 78 9786018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9786018 Reactome DB_ID: 9786015 G6B:PTPN6,PTPN11 [plasma membrane] G6B:PTPN6,PTPN11 Reactome DB_ID: 9786013 1 UniProt:D7PDD4 Mpig6b UniProt D7PDD4 18 EQUAL 241 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9779747 1 PTPN6,PTPN11 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ptpn11 [cytosol] Ptpn6 [cytosol] UniProt P35235 UniProt P29351 Reactome Database ID Release 78 9786015 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9786015 Reactome R-MMU-5684187 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684187.1 p-Y348-SYK dissociates p-Y348-SYK dissociates This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9786006 1 Reactome DB_ID: 9782977 1 O4'-phospho-L-tyrosine at 348 348 EQUAL 1 EQUAL 635 EQUAL Reactome DB_ID: 9759823 1 Reactome Database ID Release 78 9786008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9786008 Reactome R-MMU-453183 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-453183.1 Structural and biophysical studies indicate that the adaptability of the Syk tandem SH2 domains is made possible by relatively weak interactions between the two SH2 domains and the flexibility of interdomain A (Zhang et al. 2008). A large proportion of phosphorylated Syk is released into the cytosol. One factor that has been proposed for modulating the interactions of Syk with the receptor ITAM is the phosphorylation of Syk on Y130 (Keshvara et al. 1997). 18689684 Pubmed 2008 Tyr130 phosphorylation triggers Syk release from antigen receptor by long-distance conformational uncoupling Zhang, Y Oh, H Burton, RA Burgner, JW Geahlen, RL Post, CB Proc Natl Acad Sci U S A 105:11760-5 8617742 Pubmed 1996 Syk, activated by cross-linking the B-cell antigen receptor, localizes to the cytosol where it interacts with and phosphorylates alpha-tubulin on tyrosine Peters, JD Furlong, MT Asai, DJ Harrison, ML Geahlen, RL J Biol Chem 271:4755-62 inferred by electronic annotation IEA GO IEA VAV1 is a GEF for Rho/Rac family GTPases VAV1 is a GEF for Rho/Rac family GTPases This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9784040 1 VAV1 Rho/Rac effectors:GDP [cytosol] VAV1 Rho/Rac effectors:GDP Reactome DB_ID: 29420 1 Converted from EntitySet in Reactome Reactome DB_ID: 9784038 1 VAV1 effectors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Rac1 [cytosol] Rhog [cytosol] Rac2 [cytosol] UniProt P63001 UniProt P84096 UniProt Q05144 Reactome Database ID Release 78 9784040 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784040 Reactome R-MMU-114543 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114543.1 Reactome DB_ID: 29438 1 Reactome DB_ID: 29420 1 Reactome DB_ID: 9784042 1 VAV1 Rho/Rac effectors:GTP [cytosol] VAV1 Rho/Rac effectors:GTP Reactome DB_ID: 29438 1 Converted from EntitySet in Reactome Reactome DB_ID: 9784038 1 Reactome Database ID Release 78 9784042 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784042 Reactome R-MMU-114539 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114539.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9784044 UniProt:P27870 Vav1 Vav1 Vav Vav1 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 O4'-phospho-L-tyrosine at 174 (in Homo sapiens) 174 EQUAL 1 EQUAL 845 EQUAL Reactome Database ID Release 78 9784045 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784045 Reactome Database ID Release 78 9784053 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784053 Reactome R-MMU-442273 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-442273.1 Vav family members are guanine nucleotide exchange factors (GEFs) for Rho-family GTPases. Vav1 is a GEF for Rac1, Rac2 and RhoG, and possibly RhoA and Cdc42 18589439 Pubmed 2008 Structural basis of guanine nucleotide exchange mediated by the T-cell essential Vav1 Chrencik, JE Brooun, A Zhang, H Mathews, II Hura, GL Foster, SA Perry, JJ Streiff, M Ramage, P Widmer, H Bokoch, GM Tainer, JA Weckbecker, G Kuhn, P J Mol Biol 380:828-43 17054426 Pubmed 2007 Vav family proteins are required for optimal regulation of PLCgamma2 by integrin alphaIIbbeta3 Pearce, AC McCarty, OJ Calaminus, SD Vigorito, E Turner, M Watson, SP Biochem J 401:753-61 15886116 Pubmed 2005 Vav-family proteins in T-cell signalling Tybulewicz, VL Curr Opin Immunol 17:267-74 9032261 Pubmed 1997 Lck regulates Vav activation of members of the Rho family of GTPases Han, J Das, B Wei, W Van Aelst, L Mosteller, RD Khosravi-Far, R Westwick, JK Der, CJ Broek, D Mol Cell Biol 17:1346-53 8990121 Pubmed 1997 Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product Crespo, P Schuebel, KE Ostrom, AA Gutkind, JS Bustelo, XR Nature 385:169-72 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 78 9784055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784055 Reactome DB_ID: 9784051 PIP3:VAV1,2,3 [plasma membrane] PIP3:VAV1,2,3 Reactome DB_ID: 179838 1 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate PIP3 ChEBI 16618 Converted from EntitySet in Reactome Reactome DB_ID: 9783413 1 VAV1,2,3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Vav2 [cytosol] Vav3 [cytosol] Vav1 [cytosol] UniProt Q60992 UniProt Q9R0C8 Reactome Database ID Release 78 9784051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784051 Reactome R-MMU-5340329 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5340329.1 INHIBITION Reactome Database ID Release 78 9784054 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784054 Reactome DB_ID: 9784049 VAV family:PIP2 [plasma membrane] VAV family:PIP2 Converted from EntitySet in Reactome Reactome DB_ID: 9784047 1 VAV family [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Vav2 [cytosol] Vav1 [cytosol] Reactome DB_ID: 179856 1 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate PIP2 ChEBI 18348 Reactome Database ID Release 78 9784049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784049 Reactome R-MMU-434632 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-434632.1 VAV2 is a GEF for Rho/Rac family kinases VAV2 is a GEF for Rho/Rac family 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> Reactome DB_ID: 9784061 1 VAV2 Rho/Rac effectors:GDP [cytosol] VAV2 Rho/Rac effectors:GDP Reactome DB_ID: 29420 1 Converted from EntitySet in Reactome Reactome DB_ID: 9784059 1 VAV2 effectors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Rhog [cytosol] Rhob [cytosol] Rhoa [cytosol] UniProt P62746 UniProt Q9QUI0 Reactome Database ID Release 78 9784061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784061 Reactome R-MMU-442278 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-442278.1 Reactome DB_ID: 29438 1 Reactome DB_ID: 29420 1 Reactome DB_ID: 9784063 1 VAV2 Rho/Rac effectors:GTP [cytosol] VAV2 Rho/Rac effectors:GTP Converted from EntitySet in Reactome Reactome DB_ID: 9784059 1 Reactome DB_ID: 29438 1 Reactome Database ID Release 78 9784063 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784063 Reactome R-MMU-442290 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-442290.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9784066 UniProt:Q60992 Vav2 Vav2 Vav2 FUNCTION Guanine nucleotide exchange factor for the Rho family of Ras-related GTPases. Plays an important role in angiogenesis. Its recruitment by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly.SUBUNIT Interacts (via SH2 domains) with the phosphorylated form of EPHA2. Interacts with NEK3 and PRLR and this interaction is prolactin-dependent (By similarity). Interacts with SSX2IP.PTM Phosphorylated on tyrosine residues in response to FGR activation. O4'-phospho-L-tyrosine at 172 (in Homo sapiens) 172 EQUAL 1 EQUAL 878 EQUAL Reactome Database ID Release 78 9784067 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784067 Reactome Database ID Release 78 9784069 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784069 Reactome R-MMU-442291 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-442291.1 Members of the Vav family are guanine nucleotide exchange factors (GEFs) for Rho-family GTPases. Vav2 is a GEF for RhoA, RhoB and RhoG, and possibly Rac1 and Cdc42 inferred by electronic annotation IEA GO IEA VAV3 is a GEF for Rho/Rac family kinases VAV3 is a GEF for Rho/Rac family 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> Reactome DB_ID: 9784073 1 VAV3 Rho/Rac effectors:GDP [cytosol] VAV3 Rho/Rac effectors:GDP Converted from EntitySet in Reactome Reactome DB_ID: 9784071 1 VAV3 effectors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Rac1 [cytosol] Rhog [cytosol] Rhoa [cytosol] Reactome DB_ID: 29420 1 Reactome Database ID Release 78 9784073 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784073 Reactome R-MMU-442313 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-442313.1 Reactome DB_ID: 29438 1 Reactome DB_ID: 9784075 1 VAV3 Rho/Rac effectors:GTP [cytosol] VAV3 Rho/Rac effectors:GTP Converted from EntitySet in Reactome Reactome DB_ID: 9784071 1 Reactome DB_ID: 29438 1 Reactome Database ID Release 78 9784075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784075 Reactome R-MMU-442315 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-442315.1 Reactome DB_ID: 29420 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9784078 UniProt:Q9R0C8 Vav3 O4'-phospho-L-tyrosine at 173 (in Homo sapiens) 173 EQUAL 1 EQUAL 847 EQUAL Reactome Database ID Release 78 9784079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784079 Reactome Database ID Release 78 9784081 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9784081 Reactome R-MMU-442314 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-442314.1 Vav3 is a guanine nucleotide exchange factors (GEF) for RhoA, RhoB and to a lesser extent Rac1. inferred by electronic annotation IEA GO IEA 2.7.10 Syk/Lck phosphorylate LAT Syk/Lck phosphorylate LAT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9771256 1 UniProt:O54957 Lat UniProt O54957 1 EQUAL 262 EQUAL Reactome DB_ID: 29370 2 Reactome DB_ID: 9783919 1 O4'-phospho-L-tyrosine at 200 (in Homo sapiens) 200 EQUAL O4'-phospho-L-tyrosine at 220 (in Homo sapiens) 220 EQUAL 1 EQUAL 262 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9783921 p-Y348-SYK/LCK [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Syk [cytosol] Lck [cytosol] UniProt P06240 Reactome Database ID Release 78 9783922 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783922 Reactome Database ID Release 78 9783924 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783924 Reactome R-MMU-434836 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-434836.1 Activated Syk (or possibly the related kinase Lck) phosphorylates two key tyrosine residues of LAT. 11901197 Pubmed 2002 Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling Judd, BA Myung, PS Obergfell, A Myers, EE Cheng, AM Watson, SP Pear, WS Allman, D Shattil, Sanford J Koretzky, GA J Exp Med 195:705-17 16938345 Pubmed 2007 Evidence of LAT as a dual substrate for Lck and Syk in T lymphocytes Jiang, Y Cheng, H Leuk Res 31:541-5 16102042 Pubmed 2005 GPVI and integrin alphaIIb beta3 signaling in platelets Watson, SP Auger, JM McCarty, OJ Pearce, AC J Thromb Haemost 3:1752-62 inferred by electronic annotation IEA GO IEA 2.7.10 Syk activation leads to SLP-76 activation Syk activation leads to SLP-76 activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 3 Reactome DB_ID: 430203 1 UniProt:Q60787 Lcp2 Lcp2 Lcp2 FUNCTION Involved in T-cell antigen receptor mediated signaling.SUBUNIT Interacts with SHB. Interacts with PRAM1 (By similarity). Interacts with SLA (PubMed:10662792). Interacts with GRB2 (PubMed:7706237). Interacts with CBLB (PubMed:10646608). Interacts (via SH2 domain) with CD6 (via tyrosine phosphorylated C-terminus) (PubMed:16914752, PubMed:24584089). Interacts with FYB1 and the phosphorylated form of FYB2 (By similarity).TISSUE SPECIFICITY Highly expressed in spleen, thymus, and peripheral blood leukocytes.DOMAIN The SH2 domain mediates interaction with SHB.PTM Phosphorylated after T-cell receptor activation by ZAP70, ITK and TXK, which leads to the up-regulation of Th1 preferred cytokine IL-2. SYK-dependent phosphorylation is required for recruitment of PI3K signaling components (By similarity). UniProt Q60787 1 EQUAL 533 EQUAL Reactome DB_ID: 29370 3 Reactome DB_ID: 9771217 1 O4'-phospho-L-tyrosine at 113 (in Homo sapiens) 113 EQUAL O4'-phospho-L-tyrosine at 128 (in Homo sapiens) 128 EQUAL O4'-phospho-L-tyrosine at 145 (in Homo sapiens) 145 EQUAL 1 EQUAL 533 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9782977 O4'-phospho-L-tyrosine at 348 348 EQUAL 1 EQUAL 635 EQUAL Reactome Database ID Release 78 9782978 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782978 Reactome Database ID Release 78 9782980 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782980 Reactome R-MMU-429449 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-429449.1 Stimulation of platelets with collagen-related peptide leads to tyrosine phosphorylation of SLP-76, an adaptor protein with multiple binding domains (Gross et al. 1999). Phosphorylation of SLP-76 is mediated by Syk, analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996, Hussain et al. 1999, Fasbender et al. 2017). SLP-76 was shown to bind to tyrosine-phosphorylated C-terminal tail of SYK (de Castro et al. 2012). The phosphorylated tyrosine residues provide a binding site for the SH2 domains of downstream signalling proteins like Vav, Itk and ADAP (Jordan et al. 2003). Platelets from mice defective in SLP76 do not connect GPVI engagement with downstream signaling (Clements et al. 1999, Judd et al. 2000). GPVI signaling via SLP-76 does not appear to require LAT or GADS (Judd et al. 2002) suggesting that the mechanism is not identical to that of T-cells. LAT and SLP-76 are both required for P-selectin expression and degranulation but may function independently, or rely on proteins not required by T-cells (Jordan et al. 2003). 8702662 Pubmed 1996 Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function Bubeck Wardenburg, J Fu, C Jackman, JK Flotow, H Wilkinson, SE Williams, DH Johnson, R Kong, G Chan, AC Findell, PR J Biol Chem 271:19641-4 10026222 Pubmed 1999 Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets Gross, BS Lee, JR Clements, JL Turner, M Tybulewicz, VL Findell, PR Koretzky, GA Watson, SP J Biol Chem 274:5963-71 19850008 Pubmed 2009 Phosphatidylinositol-3-kinase-dependent phosphorylation of SLP-76 by the lymphoma-associated ITK-SYK fusion-protein Hussain, Alamdar Faryal, Rani Nore, Beston F Mohamed, Abdalla J Smith, C I Edvard Biochem. Biophys. Res. Commun. 390:892-6 28736554 Pubmed 2017 Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes Fasbender, Frank Claus, Maren Wingert, Sabine Sandusky, Mina Watzl, Carsten Front Immunol 8:789 22267732 Pubmed 2012 Once phosphorylated, tyrosines in carboxyl terminus of protein-tyrosine kinase Syk interact with signaling proteins, including TULA-2, a negative regulator of mast cell degranulation de Castro, Rodrigo Orlandini Zhang, Juan Groves, Jacqueline R Barbu, Emilia Alina Siraganian, Reuben P J. Biol. Chem. 287:8194-204 11050236 Pubmed 2000 Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through alpha IIb beta 3 and collagen receptors Judd, BA Myung, PS Leng, L Obergfell, A Pear, WS Shattil, Sanford J Koretzky, GA Proc Natl Acad Sci U S A 97:12056-61 12555096 Pubmed 2003 Adaptors as central mediators of signal transduction in immune cells Jordan, MS Singer, AL Koretzky, GA Nat Immunol 4:110-6 9884330 Pubmed 1999 Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice Clements, JL Lee, JR Gross, B Yang, B Olson, JD Sandra, A Watson, SP Lentz, Steven R Koretzky, GA J Clin Invest 103:19-25 16493428 Pubmed 2006 SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond Koretzky, GA Abtahian, F Silverman, MA Nat Rev Immunol 6:67-78 inferred by electronic annotation IEA GO IEA SLP-76 stimulates PLC gamma 2 SLP-76 stimulates PLC gamma 2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9782982 1 UniProt:Q8CIH5 Plcg2 Plcg2 Plcg2 FUNCTION The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. It is a crucial enzyme in transmembrane signaling.SUBUNIT Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts constitutively with THEMIS2 (PubMed:27992403).PTM Phosphorylated on tyrosine residues by BTK and SYK; upon ligand-induced activation of a variety of growth factor receptors and immune system receptors. Phosphorylation leads to increased phospholipase activity (By similarity). Phosphorylated on tyrosine residues by CSF1R. UniProt Q8CIH5 1 EQUAL 1265 EQUAL Reactome DB_ID: 9759886 1 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] 1 EQUAL 1265 EQUAL Reactome Database ID Release 78 9782984 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782984 Reactome R-MMU-429497 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-429497.1 SLP-76 has a well-established role in recruitment of PLC gamma 1 in immunoreceptor signalling; its role in the recruitment of PLC gamma 2 in integrin signalling is less clear. Results from SLP-76 null mice imply a functional role in GPVI signalling. Platelets from SLP-76 null mice exhibit a marked reduction in spreading and a decrease in whole cell phosphotyrosine levels when adhered to a fibrinogen-coated surface. In vivo reconstitution of SLP-76 by retroviral gene transfer corrects bleeding diathesis and restores normal responses to both collagen and fibrinogen (Judd et al., 2000). 12832405 Pubmed 2003 Integrin alpha IIb beta 3-dependent calcium signals regulate platelet-fibrinogen interactions under flow. Involvement of phospholipase C gamma 2 Goncalves, I Hughan, SC Schoenwaelder, SM Yap, CL Yuan, Y Jackson, SP J Biol Chem 278:34812-22 10469124 Pubmed 1999 Evidence that phospholipase C-gamma2 interacts with SLP-76, Syk, Lyn, LAT and the Fc receptor gamma-chain after stimulation of the collagen receptor glycoprotein VI in human platelets Gross, BS Melford, SK Watson, SP Eur J Biochem 263:612-23 12813055 Pubmed 2003 Signaling role for phospholipase C gamma 2 in platelet glycoprotein Ib alpha calcium flux and cytoskeletal reorganization. Involvement of a pathway distinct from FcR gamma chain and Fc gamma RIIA Mangin, P Yuan, Y Goncalves, I Eckly, A Freund, M Cazenave, JP Gachet, C Jackson, SP Lanza, F J Biol Chem 278:32880-91 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 78 9782985 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9782985 Reactome DB_ID: 9771217 O4'-phospho-L-tyrosine at 113 (in Homo sapiens) 113 EQUAL O4'-phospho-L-tyrosine at 128 (in Homo sapiens) 128 EQUAL O4'-phospho-L-tyrosine at 145 (in Homo sapiens) 145 EQUAL 1 EQUAL 533 EQUAL p-SLP-76 binds VAV p-SLP-76 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> Reactome DB_ID: 9771217 1 O4'-phospho-L-tyrosine at 113 (in Homo sapiens) 113 EQUAL O4'-phospho-L-tyrosine at 128 (in Homo sapiens) 128 EQUAL O4'-phospho-L-tyrosine at 145 (in Homo sapiens) 145 EQUAL 1 EQUAL 533 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9783413 1 Reactome DB_ID: 9783415 1 p-SLP-76:VAV [cytosol] p-SLP-76:VAV Reactome DB_ID: 9771217 1 O4'-phospho-L-tyrosine at 113 (in Homo sapiens) 113 EQUAL O4'-phospho-L-tyrosine at 128 (in Homo sapiens) 128 EQUAL O4'-phospho-L-tyrosine at 145 (in Homo sapiens) 145 EQUAL 1 EQUAL 533 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9783413 1 Reactome Database ID Release 78 9783415 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783415 Reactome R-MMU-430155 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-430155.1 Reactome Database ID Release 78 9783417 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783417 Reactome R-MMU-430158 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-430158.1 SLP-76 is a hematopoietic cell-specific adapter protein. Studies indicate that three phosphotyrosines in SLP-76 (Y113, Y128, and Y145) are required for interactions with the SH2 domains of Vav1 (and Nck and Itk). This interaction is essential for membrane recruitment of Vav1. Similarly, association of Vav3 with SLP-76 was found to be essential for membrane recruitment. Vav2 has been shown to interact with SLP-76 in resting Jurkat cells. 8673706 Pubmed 1996 Vav and SLP-76 interact and functionally cooperate in IL-2 gene activation Wu, J Motto, DG Koretzky, GA Weiss, A Immunity 4:593-602 11607831 Pubmed 2001 The role of the adapter molecule SLP-76 in platelet function Judd, BA Koretzky, GA Oncogene 20:6291-9 11262396 Pubmed 2001 Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte Tartare-Deckert, S Monthouel, MN Charvet, C Foucault, I Van Obberghen, E Bernard, A Altman, A Deckert, M J Biol Chem 276:20849-57 15708849 Pubmed 2005 Membrane localization and function of Vav3 in T cells depend on its association with the adapter SLP-76 Charvet, C Canonigo, AJ Billadeau, DD Altman, A J Biol Chem 280:15289-99 inferred by electronic annotation IEA GO IEA 3.1.4.3 PLC gamma 2-mediated PIP2 hydrolysis PLC gamma 2-mediated PIP2 hydrolysis This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 179856 1 Reactome DB_ID: 114519 1 1,2-diacyl-sn-glycerol [ChEBI:17815] 1,2-diacyl-sn-glycerol ChEBI 17815 Reactome DB_ID: 114520 1 1D-myo-inositol 1,4,5-trisphosphate [ChEBI:16595] 1D-myo-inositol 1,4,5-trisphosphate ChEBI 16595 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9759886 phosphorylated residue at unknown position 1 EQUAL 1265 EQUAL GO 0004629 GO molecular function Reactome Database ID Release 78 9759887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759887 Reactome Database ID Release 78 9759907 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759907 Reactome R-MMU-114689 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-114689.1 At the beginning of this reaction, 1 molecule of '1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate' is present. At the end of this reaction, 1 molecule of '1D-myo-Inositol 1,4,5-trisphosphate', and 1 molecule of '1,2-Diacylglycerol' are present.<br><br> This reaction is mediated by the 'phospholipase C activity' of 'Phosphorylated phospholipase C gamma 2'.<br> 2841328 Pubmed 1988 Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human platelets Banno, Y Yada, Y Nozawa, Y J Biol Chem 263:11459-65 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 78 9759908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759908 Reactome DB_ID: 9759905 p-Y7-CLEC1B dimer:PDPN:SYK [plasma membrane] p-Y7-CLEC1B dimer:PDPN:SYK Reactome DB_ID: 9759903 1 1 EQUAL 635 EQUAL Reactome DB_ID: 9759900 1 p-Y7-CLEC1B dimer:PDPN [plasma membrane] p-Y7-CLEC1B dimer:PDPN Reactome DB_ID: 9759894 1 p-Y7-CLEC1B dimer [plasma membrane] p-Y7-CLEC1B dimer Reactome DB_ID: 9759892 2 UniProt:Q9JL99 Clec1b UniProt Q9JL99 O4'-phospho-L-tyrosine at 7 (in Homo sapiens) 7 EQUAL 1 EQUAL 229 EQUAL Reactome Database ID Release 78 9759894 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759894 Reactome R-MMU-5684808 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684808.1 Reactome DB_ID: 9759898 1 UniProt:Q62011 Pdpn UniProt Q62011 23 EQUAL 162 EQUAL Reactome Database ID Release 78 9759900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759900 Reactome R-MMU-5684816 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684816.1 Reactome Database ID Release 78 9759905 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9759905 Reactome R-MMU-5684799 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684799.1 GPVI stimulates PI3K beta, gamma GPVI stimulates PI3K beta, gamma This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759933 1 Reactome DB_ID: 9783968 1 PI3K beta [cytosol] PI3K beta Reactome DB_ID: 9756244 1 UniProt:Q8BTI9 Pik3cb Pik3cb Pik3cb FUNCTION Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) derivatives at position 3 of the inositol ring to produce 3-phosphoinositides. Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (By similarity). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors.PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CB and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interaction with PIK3R2 is required for nuclear localization and nuclear export (By similarity). Part of a complex with PIK3R1 and PTEN (By similarity). Binding to PTEN may antagonize the lipid kinase activity under normal growth conditions (By similarity). Part of a complex involved in autophagosome formation composed of PIK3C3 and PIK3R4. Interacts with BECN1, ATG14 and RAB5A.DOMAIN The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1; the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1; and the PI3K/PI4K kinase domain with the cSH2 (C-terminal SH2) region of PIK3R1. The inhibitory interaction between the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1 is weak. The nuclear localization signal (NLS) is required for its function in cell survival (By similarity).PTM Phosphorylation at Ser-1064 down-regulates lipid kinase activity.DISRUPTION PHENOTYPE Mice have defects in autophagosome formation. Have normal bleeding time but are resistant to thrombosis after arterial injury. Mice fail to induce tumors in a model of prostate tumor formation induced by Pten loss.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt Q8BTI9 1 EQUAL 1070 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9759603 1 PI3K-regulatory subunits [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Pik3r1 [cytosol] Reactome Database ID Release 78 9783968 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783968 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 Reactome DB_ID: 9780389 1 PI3K gamma [cytosol] PI3K gamma Reactome DB_ID: 9027212 1 UniProt:Q9JHG7 Pik3cg Pik3cg Pik3cg Pi3kg1 FUNCTION Phosphoinositide-3-kinase (PI3K) 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. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to GRK2 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contribute to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis (By similarity).ACTIVITY REGULATION Activated by both the alpha and the beta-gamma G proteins following stimulation of G protein-coupled receptors (GPCRs). Activation by GPCRs is assisted by the regulatory subunit PIK3R5 leading to the translocation from the cytosol to the plasma membrane and to kinase activation; the respective activation involving PIK3R6 requires HRAS for membrane recruitment. Wortmannin sensitive in nM range. Inhibited by AS252424.PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CG and a PIK3R5 or PIK3R6 regulatory subunit. Interacts with GRK2 through the PIK helical domain (By similarity). Interaction with GRK2 is required for targeting to agonist-occupied receptor. Interacts with PDE3B. Interacts with TPM2 (By similarity). Interacts with EPHA8; regulates integrin-mediated cell adhesion to substrate. Interacts with HRAS; the interaction is required for membrane recruitment and beta-gamma G protein dimer-dependent activation of the PI3K gamma complex PIK3CG:PIK3R6.PTM Phosphorylated at Thr-1024 by PKA. Phosphorylation inhibits lipid kinase activity.DISRUPTION PHENOTYPE Viable and fertile. Display abnormalities when the immune system is stressed. Reduced leukocyte migration in response to chemotactic agents and towards the site of inflammation. Reduced neutrophil oxidative burst in response to chemotactic agents. Reduced thymocyte survival and defective T lymphocyte activation. Protected from leukocyte infiltration of synovia in a model of rheumatoid arthritis. Dendritic cell showed reduced response to chemokines and migration to draining lymph nodes under inflammatory conditions. Platelets have defects in thrombus formation. Increased cardiac contractility. Display myocardial damage after transverse aortic constriction.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt Q9JHG7 1 EQUAL 1102 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9780387 1 PI3-kinase gamma, regulatory subunit [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Pik3r5 [cytosol] Pik3r6 [cytosol] UniProt Q5SW28 UniProt Q3U6Q4 Reactome Database ID Release 78 9780389 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9780389 Reactome R-MMU-392291 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-392291.1 Reactome Database ID Release 78 9783970 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783970 Reactome R-MMU-437118 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-437118.1 GPVI downstream signaling involves PI3K. Mouse knockouts of PI3Kbeta/PI3Kgamma suggest that though both isoforms are required for a full platelet response, only beta is absolutely required for Akt phosphorylation, Rap1 activation, and platelet aggregation downstream. The pathway connecting GPVI to PI3K is unclear. Two possible routes are suggested by interactions of the PI3K p85 regulatory subunit with LAT and with peptides representing the ITAM motif of Fc Epsilon R1 gamma. 19515725 Pubmed 2009 Genetic evidence for a predominant role of PI3Kbeta catalytic activity in ITAM- and integrin-mediated signaling in platelets Canobbio, I Stefanini, L Cipolla, L Ciraolo, E Gruppi, C Balduini, C Hirsch, E Torti, M Blood 114:2193-6 19700402 Pubmed 2009 The role of PI 3-K{beta} in glycoprotein VI-mediated akt activation in platelets Kim, S Mangin, P Dangelmaier, C Lillian, R Jackson, SP Daniel, JL Kunapuli, SP J Biol Chem 9852111 Pubmed 1998 The p85 subunit of phosphatidylinositol 3-kinase associates with the Fc receptor gamma-chain and linker for activitor of T cells (LAT) in platelets stimulated by collagen and convulxin Gibbins, JM Briddon, S Shutes, A van Vugt, MJ van de Winkel, JG Saito, T Watson, SP J Biol Chem 273:34437-43 inferred by electronic annotation IEA GO IEA 2.7.1.153 PI3K alpha, beta, gamma convert PIP2 to PIP3 PI3K alpha, beta, gamma convert PIP2 to PIP3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 179856 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 179838 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9783985 PI3K alpha, beta, gamma [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0046934 GO molecular function Reactome Database ID Release 78 9783986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783986 Reactome Database ID Release 78 9783988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783988 Reactome R-MMU-437162 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-437162.1 Class I Phosphoinositide 3-kinases (PI3Ks) are heterodimeric proteins, each having a catalytic subunit of 110-120 kDa and an associated regulatory subunit. PI3Ks alpha, beta and delta share a common regulatory p85 subunit, PI3K gamma has a p101 regulatory subunit. All the class I PI3Ks are able to phosphorylate PtdIns, PtdIns-4-P, or PtdIns-4,5-P2 (PIP2) on the free 3-position, and have a strong preference for PIP2.They are activated by receptor tyrosine kinases and by Ras and Rho family GTPases. 7624799 Pubmed 1995 Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase Stoyanov, B Volinia, S Hanck, T Rubio, I Loubtchenkov, M Malek, D Stoyanova, S Vanhaesebroeck, B Dhand, R Nurnberg, B Science 269:690-3 17371249 Pubmed 2007 Regulation of class IA PI3Ks Wu, H Yan, Y Backer, JM Biochem Soc Trans 35:242-4 9759495 Pubmed 1998 Phosphoinositide kinases Fruman, DA Meyers, RE Cantley, Lewis C Annu Rev Biochem 67:481-507 8246984 Pubmed 1993 Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85 Hu, P Mondino, A Skolnik, EY Schlessinger, J Mol Cell Biol 13:7677-88 inferred by electronic annotation IEA GO IEA PIP3 recruits PDPK1 to the membrane PIP3 recruits PDPK1 to the membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9771052 1 UniProt:Q9Z2A0 Pdpk1 UniProt Q9Z2A0 1 EQUAL 556 EQUAL Reactome DB_ID: 179838 1 Reactome DB_ID: 9758217 1 PDPK1:PIP3 [plasma membrane] PDPK1:PIP3 Reactome DB_ID: 9758215 1 1 EQUAL 556 EQUAL Reactome DB_ID: 179838 1 Reactome Database ID Release 78 9758217 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9758217 Reactome R-MMU-109697 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109697.1 Reactome Database ID Release 78 9811753 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9811753 Reactome R-MMU-2316429 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2316429.1 PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999). 9895304 Pubmed 1999 Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1 Currie, RA Walker, KS Gray, A Deak, M Casamayor, A Downes, CP Cohen, P Alessi, DR Lucocq, J Biochem J 337:575-83 inferred by electronic annotation IEA GO IEA G6B binds PTPN6,PTPN11 G6B binds PTPN6,PTPN11 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9786013 1 18 EQUAL 241 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9779747 1 Reactome DB_ID: 9786015 1 Reactome Database ID Release 78 9829282 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829282 Reactome R-MMU-5684169 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684169.1 G6B is a member of the immunoglobulin superfamily. The G6B-B variant is the only variant to contain both a transmembrane region and two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that support binding to the SH2 domain-containing protein tyrosine phosphatases PTPN6 (SHP1) and PTPN11 (SHP2) (de Vet et al. 2001, Senis et al. 2007). ITIMs are defined by the consensus sequence (L/I/V/S)-X-Y-X-X-(L/V) and are commonly present in pairs separated by 15 to 30 amino acid residues. ITIM-containing receptors were originally identified by their ability to inhibit signaling by ITAM receptors (Bijsterbosch & Klaus 1985). Expression of the GPVI-FcR gamma-chain complex orC-type lectin domain family 1 member B (CLEC1B, CLEC2) in DT40 (chicken) B cells leads to the generation of both constitutive and agonist-induced signals that are inhibited by G6B. This effect is dependent on the two ITIMs in the cytosolic tail of G6B, but is reported to be independent of the two SH2 domain-containing tyrosine phosphatases PTPN6 and PTPN11, and the inositol lipid 5”²-phosphatase SHIP1 (Mori et al. 2008). A more recent study (Coxon et al. 2011) found that other SH2 domain-containing proteins including SYK and PLCgamma2 also recognize G6B phosphomotifs, which may explain why G6B remains inhibitory in the absence of both PTPN6 and PTPN11. <br><br>The tandem SH2 domains of PTPN11 have a 100-fold higher binding affinity for G6B than that of PTPN6. PTPN6 has an absolute binding requirement for phosphorylation at both ITAM motifs, while PTPN11 can associate with G6B when only one motif is phosphorylated. The presence of dual phosphorylated G6B in washed human platelets reduced the EC(50) for both CRP and collagen-induced aggregation (Coxon et al. 2011). G6B is proposed to inhibit sustained constitutive signaling from GPVI-FcRgamma and CLEC1B (Mori et al. 2008). 17186946 Pubmed 2007 A comprehensive proteomics and genomics analysis reveals novel transmembrane proteins in human platelets and mouse megakaryocytes including G6b-B, a novel immunoreceptor tyrosine-based inhibitory motif protein Senis, Yotis A Tomlinson, Michael G García, Angel Dumon, Stephanie Heath, Victoria L Herbert, John Cobbold, Stephen P Spalton, Jennifer C Ayman, Sinem Antrobus, Robin Zitzmann, Nicole Bicknell, R Frampton, Jon Authi, Kalwant S Martin, Ashley Wakelam, Michael J O Watson, Stephen P Mol. Cell Proteomics 6:548-64 3877778 Pubmed 1985 Crosslinking of surface immunoglobulin and Fc receptors on B lymphocytes inhibits stimulation of inositol phospholipid breakdown via the antigen receptors Bijsterbosch, M K Klaus, G G J. Exp. Med. 162:1825-36 23185356 Pubmed 2012 An investigation of hierachical protein recruitment to the inhibitory platelet receptor, G6B-b Coxon, Carmen H Sadler, Amanda J Huo, Jiandong Campbell, RD PLoS ONE 7:e49543 11544253 Pubmed 2001 G6b, a novel immunoglobulin superfamily member encoded in the human major histocompatibility complex, interacts with SHP-1 and SHP-2 de Vet, E C Aguado, B Campbell, R D J. Biol. Chem. 276:42070-6 inferred by electronic annotation IEA GO IEA CLEC1B dimer binds PDPN CLEC1B dimer binds PDPN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759898 1 23 EQUAL 162 EQUAL Reactome DB_ID: 9829314 1 CLEC1B dimer [plasma membrane] CLEC1B dimer Reactome DB_ID: 9829312 2 1 EQUAL 229 EQUAL Reactome Database ID Release 78 9829314 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829314 Reactome R-MMU-5684807 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684807.1 Reactome DB_ID: 9829316 1 CLEC1B dimer:PDPN [plasma membrane] CLEC1B dimer:PDPN Reactome DB_ID: 9759898 1 23 EQUAL 162 EQUAL Reactome DB_ID: 9829314 1 Reactome Database ID Release 78 9829316 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829316 Reactome R-MMU-5684824 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684824.1 Reactome Database ID Release 78 9829320 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829320 Reactome R-MMU-5684836 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684836.1 C-type lectin domain family 1 member B (CLEC1B, CLEC2) is a 32-kDa C-type lectin-like receptor that dimerizes to form the platelet receptor for the snake venom toxin rhodocytin and the endogenous lymphatic endothelial marker, podoplanin (PDPN) (Suzuki-Inoue et al. 2006, 2007, Christou et al. 2008, Watson et al. 2009). PDPN is a sialomucin-like glycoprotein with a wide tissue distribution. It is found at a high level in lung type I alveolar cells, kidney podocytes, choroid plexus epithelium, lymphatic endothelial cells and fibroblastic reticular cells within secondary lymphoid organs. PDPN is not found on vascular endothelial cells. It is up-regulated in a variety of tumors and on macrophages following lipopolysaccharide stimulation. Cells expressing PDPN or recombinant forms of its extracellular domain have been shown to induce platelet activation (Pollitt et al. 2014). 25368330 Pubmed 2014 Syk and Src family kinases regulate C-type lectin receptor 2 (CLEC-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells Pollitt, Alice Y Poulter, Natalie S Gitz, Eelo Navarro-Nuñez, Leyre Wang, Ying-Jie Hughes, Craig E Thomas, Steven G Nieswandt, Bernhard Douglas, Michael R Owen, Dylan M Jackson, David G Dustin, Michael L Watson, Steve P J. Biol. Chem. 289:35695-710 16174766 Pubmed 2006 A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2 Suzuki-Inoue, Katsue Fuller, Gemma L J García, Angel Eble, Johannes A Pöhlmann, Stefan Inoue, Osamu Gartner, T Kent Hughan, Sascha C Pearce, Andrew C Laing, Gavin D Theakston, R David G Schweighoffer, Edina Zitzmann, Nicole Morita, Takashi Tybulewicz, Victor L J Ozaki, Yukio Watson, Steve P Blood 107:542-9 18215137 Pubmed 2008 Renal cells activate the platelet receptor CLEC-2 through podoplanin Christou, Charita M Pearce, Andrew C Watson, Aleksandra A Mistry, Anita R Pollitt, Alice Y Fenton-May, Angharad E Johnson, Louise A Jackson, David G Watson, Steve P O'Callaghan, Chris A Biochem. J. 411:133-40 19824697 Pubmed 2009 The platelet receptor CLEC-2 is active as a dimer Watson, Aleksandra A Christou, Charita M James, John R Fenton-May, Angharad E Moncayo, Gerald E Mistry, Anita R Davis, Simon J Gilbert, Robert J C Chakera, Aron O'Callaghan, Chris A Biochemistry 48:10988-96 17616532 Pubmed 2007 Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells Suzuki-Inoue, Katsue Kato, Yukinari Inoue, Osamu Kaneko, Mika Kato Mishima, Kazuhiko Yatomi, Yutaka Yamazaki, Yasuo Narimatsu, Hisashi Ozaki, Yukio J. Biol. Chem. 282:25993-6001 inferred by electronic annotation IEA GO IEA Unknown kinase phosphorylates CLEC1B dimer:PDPN Unknown kinase phosphorylates CLEC1B dimer:PDPN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9829316 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9759900 1 Reactome Database ID Release 78 9829318 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829318 Reactome R-MMU-5684806 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684806.1 Following stimulation by rhodocytin CLEC1B is phosphorylated on the YxxL or hemi-ITAM motif. The kinase responsible for this is not clear. Phosphorylation is suggested to allow the tandem SH2 domains of SYK to bind phosphorylated CLEC1B hemi-ITAM sites (Suzuki-Inoue et al. 2006). GPVI ITAMs are phosphorylated by the Src family kinases FYN and LYN, which results in SYK binding, but CLEC1B appears to be phosphorylated mainly by SYK. The SYK-specific inhibitor R406 inhibits CLEC1B phosphorylation in response to rhodocytin, suggesting SYK is responsible for hemi-ITAM phosphorylation in human platelets (Spalton et al. 2009). However the Src family-specific kinase inhibitor PP2 also inhibits CLEC1B tyrosine phosphorylation (Suzuki-Inoue et al. 2006), suggesting that CLEC1B is phosphorylated by Syk and Src family kinases in human platelets (Suzuki-Inoue et al. 2006, Suzuki-Inoue 2011). Severin et al. (2011) reported that phosphorylation of CLEC1B by rhodocytin is abolished in Syk-deficient mice, while phosphorylation is not altered in mice deficient in the major platelet Src family kinases Fyn, Lyn, Src, or the tyrosine phosphatase CD148, which regulates the basal activity of Src family kinases. The same group also reported that PP2 does not inhibit phosphorylation of mouse Clec1b by rhodocytin, in contrast to the reported effect in human platelets (Suzuki-Inoue et al. 2006), suggesting that Syk phosphorylates Clec1b independently of the Src family kinases in mice. 17339324 Pubmed 2007 The C-type lectin receptors CLEC-2 and Dectin-1, but not DC-SIGN, signal via a novel YXXL-dependent signaling cascade Fuller, Gemma L J Williams, Jennifer A E Tomlinson, Michael G Eble, Johannes A Hanna, Sheri L Pöhlmann, Stefan Suzuki-Inoue, Katsue Ozaki, Yukio Watson, Steve P Pearce, Andrew C J. Biol. Chem. 282:12397-409 21098033 Pubmed 2011 Syk-dependent phosphorylation of CLEC-2: a novel mechanism of hem-immunoreceptor tyrosine-based activation motif signaling Séverin, Sonia Pollitt, Alice Y Navarro-Nuñez, Leyre Nash, Craig A Mourão-Sá, Diego Eble, Johannes A Senis, Yotis A Watson, Steve P J. Biol. Chem. 286:4107-16 21693546 Pubmed 2011 Essential in vivo roles of the platelet activation receptor CLEC-2 in tumour metastasis, lymphangiogenesis and thrombus formation Suzuki-Inoue, Katsue J. Biochem. 150:127-32 19422460 Pubmed 2009 The novel Syk inhibitor R406 reveals mechanistic differences in the initiation of GPVI and CLEC-2 signaling in platelets Spalton, J C Mori, J Pollitt, A Y Hughes, C E Eble, J A Watson, S P J. Thromb. Haemost. 7:1192-9 inferred by electronic annotation IEA GO IEA p-Y7-CLEC1B dimer:PDPN binds SYK p-Y7-CLEC1B dimer:PDPN binds SYK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9759903 1 1 EQUAL 635 EQUAL Reactome DB_ID: 9759900 1 Reactome DB_ID: 9759905 1 Reactome Database ID Release 78 9829310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9829310 Reactome R-MMU-5684801 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5684801.1 Following the phosphorylation of CLEC1B on its hemi-ITAM motif it can bind the kinase SYK (Suzuki-Inoue et al. 2006, 2007, Spalton et al. 2009, Severin et al. 2011). Beyond SYK, CLEC1B signalling is similar to that of GPVI:FcR1 gamma. Murine platelets deficient in Syk or PLC gamma 2 fail to respond to rhodocytin, suggesting they are crucial for Clec1b signal transduction. Mice deficient in the adaptor proteins Linker for activation of T-cells family member 1 (LAT), LCP2 (SLP-76) or the guanine nucleotide exchange factors Vav1-3 are able to respond to high concentrations of rhodocytin, suggesting that these molecules participate in Clec1b signaling but do not prevent signaling when absent (Suzuki-Inoue et al. 2006, Finney et al. 2011). <br><br>Clec1b signaling is reduced in the presence of the ITIM-containing immunoglobulin superfamily transmembrane protein G6B (Mori et al. 2008). G6B is thought to act by reducing Syk tyrosine phosphorylation (Mori et al. 2008) but it is possible that the target of inhibition is elsewhere in the CLEC1B signaling cascade. 22186994 Pubmed 2012