BioPAX pathway converted from "Interleukin-3, Interleukin-5 and GM-CSF signaling" in the Reactome database. Interleukin-3, Interleukin-5 and GM-CSF signaling Interleukin-3, Interleukin-5 and GM-CSF signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> The receptor is activated The receptor is activated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9852287 2 plasma membrane GO 0005886 High affinity binding complexes of interleukin receptors using the Common beta chain [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome http://www.reactome.org Converted from EntitySet in Reactome Reactome DB_ID: 9852225 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2 [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 82 9852289 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852289 Reactome R-MMU-879942 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879942.1 Upon ligand binding to the alpha subunit, the alpha and Bc subunits asociate, forming a high affinity receptor. Subsequent signaling may require a disulfide-linked association between the alpha and beta chains (Stomski et al. 1996). While the formation of a 1:1:1 complex of interleukin:alpha subunit:common beta subunit represents a high-affinity binding complex, receptor activation involves the formation of higher order multimeric structures. The stoichiometry of endogenous active receptor complexes is not clear, but studies using dominant-negative, chimeric, and mutant receptors and modeling studies all suggest that a minimum of two Bc subunits are required for receptor activation and signaling (Guthridge et al. 1998, Hansen et al. 2008).<br><br> The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One such site is Y766, numbered according to the Uniprot canonical sequence. Note that in many publications this position is numbered as 750, referring to the mature sequence with signal peptide removed. These phosphorylations are mediated by receptor-associated kinases with JAK2 as the most likely candidate (Quelle et al. 1994, Guthridge et al. 1998). Specific phosphorylations appear to mediate association with different signaling components (Sato et al. 1993), e.g. substitution of F for Y766 prevents Shc phosphorylation (Inhorn et al. 1995) but not JAK2 phosphorylation. Modeling and structural data suggest that the active receptor is at least a dimer of ligand:alpha subunit:common beta subunit complexes (Bagley et al. 1997, Guthridge et al. 1998, Hansen et al. 2008). This fits a model of receptor activation whereby dimerization leads to Jak2 activation by transphosphorylation of the activation sites (Ihle et al. 1995, Guthridge et al. 1998, Hansen et al. 2008), leading to Bc activation by phosphorylation. The active receptors are represented here as dimers of ligand:alpha subunit:common beta subunit complexes. 1400495 Pubmed 1992 Tyrosine phosphorylation of receptor beta subunits and common substrates in response to interleukin-3 and granulocyte-macrophage colony-stimulating factor Duronio, V Clark-Lewis, I Federsppiel, B Wieler, JS Schrader, JW J Biol Chem 267:21856-63 7612228 Pubmed 1995 Signaling through the hematopoietic cytokine receptors Ihle, JN Witthuhn, BA Quelle, FW Yamamoto, K Silvennoinen, O Annu Rev Immunol 13:369-98 8649415 Pubmed 1996 Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding Stomski, FC Sun, Q Bagley, CJ Woodcock, J Goodall, G Andrews, RK Berndt, MC Lopez, Angel Mol Cell Biol 16:3035-46 9057626 Pubmed 1997 The structural and functional basis of cytokine receptor activation: lessons from the common beta subunit of the granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 receptors Bagley, CJ Woodcock, JM Stomski, FC Lopez, Angel Blood 89:1471-82 18692472 Pubmed 2008 The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation Hansen, G Hercus, TR McClure, BJ Stomski, FC Dottore, M Powell, J Ramshaw, H Woodcock, JM Xu, Y Guthridge, M McKinstry, WJ Lopez, Angel Parker, MW Cell 134:496-507 1396555 Pubmed 1992 Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation Sakamaki, K Miyajima, I Kitamura, T Miyajima, A EMBO J 11:3541-9 2681215 Pubmed 1989 Interleukin-3 stimulates the tyrosine phosphorylation of the 140-kilodalton interleukin-3 receptor Sorensen, P Mui, AL Krystal, G J Biol Chem 264:19253-8 7567993 Pubmed 1995 Identification of a viability domain in the granulocyte/macrophage colony-stimulating factor receptor beta-chain involving tyrosine-750 Inhorn, RC Carlesso, N Durstin, M Frank, DA Griffin, JD Proc Natl Acad Sci U S A 92:8665-9 8007942 Pubmed 1994 JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region Quelle, FW Sato, N Witthuhn, BA Inhorn, RC Eder, M Miyajima, A Griffin, JD Ihle, JN Mol Cell Biol 14:4335-41 9422786 Pubmed 1998 Identification of a Cys motif in the common beta chain of the interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 receptors essential for disulfide-linked receptor heterodimerization and activation of all three receptors Stomski, FC Woodcock, JM Zacharakis, B Bagley, CJ Sun, Q Lopez, Angel J Biol Chem 273:1192-9 9766809 Pubmed 1998 Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors Guthridge, MA Stomski, FC Thomas, D Woodcock, JM Bagley, CJ Berndt, MC Lopez, Angel Stem Cells 16:301-13 8647804 Pubmed 1996 Evidence for a physical association between the Shc-PTB domain and the beta c chain of the granulocyte-macrophage colony-stimulating factor receptor Pratt, JC Weiss, M Sieff, CA Shoelson, SE Burakoff, SJ Ravichandran, KS J Biol Chem 271:12137-40 8223433 Pubmed 1993 Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling Sato, N Sakamaki, K Terada, N Arai, K Miyajima, A EMBO J 12:4181-9 inferred by electronic annotation IEA GO IEA 2.7.10.2 JAK2 is phosphorylated, activated JAK2 is phosphorylated, activated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9852225 1 Reactome DB_ID: 113592 6 cytosol GO 0005829 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 29370 6 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Converted from EntitySet in Reactome Reactome DB_ID: 9852259 1 High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9852225 GO 0004715 GO molecular function Reactome Database ID Release 82 9852260 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852260 Reactome Database ID Release 82 9852262 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852262 Reactome R-MMU-879910 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879910.1 JAK2 is tyrosine phosphorylated in response to IL-3 (Silvennoinen et al. 1993), GM-CSF (Quelle et al. 1994) and IL-5 (Cornelis et al. 1995) leading to kinase activity. Although structures of JAK kinase domains exist (e.g. Lucet et al. 2006) no complete structures of Janus kinases (JAKs) are available and the activation mechanism is poorly understood. Activation is believed to be a consequence of conformational changes, propagated from conformational changes in the common beta chain (Bc) following alpha-beta dimerization. This is believed to result in a trans-activation event whereby JAKs bound to activated, dimerized receptors phosphorylate and thereby activate each other (Quelle et al. 1994, Hou et al. 2002). This model is similar to IL2R activation of JAK1/3. In addition to the observed activation of JAK2 following stimulation with IL-3, IL-5 or GM-CSF, other supporting observations include: phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006) and autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the critical Y1007 phosphorylation is represented for this reaction.<br><br>Constitutive activation of JAK2 resulting from the V617F mutation is present in over 95% of Polycythemia Vera patients (Dusa et al. 2010). F595 is indispensible for constitutive activation by V617F, but not for JAK2 activation, suggesting that this is not part of the cytokine-induced mechansim of JAK2 activation. 15143188 Pubmed 2004 Tyrosine phosphorylation of Jak2 in the JH2 domain inhibits cytokine signaling Feener, EP Rosario, F Dunn, SL Stancheva, Z Myers MG, Jr Mol Cell Biol 24:4968-78 15143187 Pubmed 2004 Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity Argetsinger, LS Kouadio, JL Steen, H Stensballe, A Jensen, ON Carter-Su, C Mol Cell Biol 24:4955-67 8378315 Pubmed 1993 Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction Silvennoinen, O Witthuhn, BA Quelle, FW Cleveland, JL Yi, T Ihle, JN Proc Natl Acad Sci U S A 90:8429-33 7542592 Pubmed 1995 Characterization of critical residues in the cytoplasmic domain of the human interleukin-5 receptor alpha chain required for growth signal transduction Cornelis, S Fache, I Van der Heyden, J Guisez, Y Tavernier, J Devos, R Fiers, W Plaetinck, G Eur J Immunol 25:1857-64 16174768 Pubmed 2006 The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor Lucet, IS Fantino, E Styles, M Bamert, R Patel, O Broughton, SE Walter, M Burns, CJ Treutlein, H Wilks, AF Rossjohn, J Blood 107:176-83 20304997 Pubmed 2010 Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity Argetsinger, LS Stuckey, JA Robertson, SA Koleva, RI Cline, JM Marto, JA Myers MG, Jr Carter-Su, C Mol Endocrinol 24:1062-76 12479803 Pubmed 2002 The Jak/STAT pathway in model organisms: emerging roles in cell movement Hou, SX Zheng, Z Chen, X Perrimon, N Dev Cell 3:765-78 20585391 Pubmed 2010 JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors Dusa, A Mouton, C Pecquet, C Herman, M Constantinescu, SN PLoS One 5:e11157 9111318 Pubmed 1997 Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop Feng, J Witthuhn, BA Matsuda, T Kohlhuber, F Kerr, IM Ihle, JN Mol Cell Biol 17:2497-501 inferred by electronic annotation IEA GO IEA STAT5 is recruited by JAK2 STAT5 is recruited by JAK2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9850269 3 STAT5A,STAT5B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Stat5a [cytosol] Stat5b [cytosol] Mus musculus NCBI Taxonomy 10090 UniProt P42230 UniProt P42232 Converted from EntitySet in Reactome Reactome DB_ID: 9852259 1 Converted from EntitySet in Reactome Reactome DB_ID: 9852248 1 High affinity binding complex dimers of cytokine receptors using Bc. activated JAK2:STAT5 [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 82 9852283 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852283 Reactome R-MMU-879930 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879930.1 Activated JAK2 binds to unphosphorylated STAT5; cytokine treatment of cells leads to JAK2 activation and promotes binding of JAK2 to unphosphorylated STAT5.<br><br><br>STAT5 proteins are considered the main targets of IL-3, IL-5 and GM-CSF signaling (Mui et al. 1995a, Mui et al. 1995b, Ihle, 2001), but other members of this family including STAT3 and STAT1 (Chin et al. 1996) can be involved, the STAT family member activated appears to depend on the cell line used in the study, rather than the cytokine (Reddy et al. 2000). IL-5 and GM-CSF increase STAT3 and 5 signaling (Caldenhoven et al. 1995, Stout et al. 2004). <br><br><br>Unphosphorylated STATs are cytoplasmic; tyrosine phosphorylation facilitates dimerization and translocation to the nucleus where they act as transcription factors. STATs were originally described as ligand-induced transcription factors in interferon-treated cells, subsequently they were shown to be critical in many signal transduction pathways associated with cytokines and neurokines including several interleukins, the interferons, erythropoietin, prolactin, growth hormone, oncostatin M (OSM), and ciliary neurotrophic factor (Darnell 1997, Reddy et al. 2000). JAK-STAT signaling is widely accepted as a primary signaling route for receptors that share the common beta subunit (Bc). <br>The role of the receptor itself in STAT5 binding is somewhat controversial because while STAT proteins can be recruited to tyrosine phosphorylated receptors via their SH2 domains (Greenlund et al. 1995, Li et al. 1997) binding of STAT5 to Bc has not been formally demonstrated (Guthridge et al. 1998), though tyrosine-phosphorylated peptides of Bc have been demonstrated to associate with STAT5, and anti-Bc or phosphotyrosine antibodies inhibited GM-CSF induced STAT5 DNA binding activity (Sakurai et al. 2000). Binding of JAK2 to STAT5 can occur in vitro when no receptor is present (Flores-Morales et al. 1998). STAT5 activation was seen when all six conserved cytoplasmic tyrosines in Bc were mutated to P (Okuda et al. 1997), but a C-terminal deletion mutant of Bc while able to activate JAK2 was unable to activate STAT5 (Smith et al. 1997). These observations suggest that JAK2 activation is a critical step in STAT signaling from Bc-containing receptors, but other factors may be required. It is not clear whether Bc is directly involved or not in STAT5 activation, but the specificity for particular STAT members is believed to be determined by STAT docking sites present on the receptor molecules, not JAK kinase preference (Reddy et al. 2000). 9121453 Pubmed 1997 Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling Li, X Leung, S Kerr, IM Stark, GR Mol Cell Biol 17:2048-56 9630227 Pubmed 1998 Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses Teglund, S McKay, C Schuetz, E van Deursen, JM Stravopodis, D Wang, D Brown, M Bodner, S Grosveld, G Ihle, JN Cell 93:841-50 8614832 Pubmed 1996 Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1 Chin, YE Kitagawa, M Su, WC You, ZH Iwamoto, Y Fu, XY Science 272:719-22 9389692 Pubmed 1997 Signaling functions of the tyrosine residues in the betac chain of the granulocyte-macrophage colony-stimulating factor receptor Okuda, K Smith, L Griffin, JD Foster, R Blood 90:4759-66 9034328 Pubmed 1997 Cytoplasmic domains of the common beta-chain of the GM-CSF/IL-3/IL-5 receptors that are required for inducing differentiation or clonal suppression in myeloid leukaemic cell lines Smith, A Metcalf, D Nicola, NA EMBO J 16:451-64 7720707 Pubmed 1995 Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs Mui, AL Wakao, H O'Farrell, AM Harada, N Miyajima, A EMBO J 14:1166-75 10851052 Pubmed 2000 IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled Reddy, EP Korapati, A Chaturvedi, P Rane, S Oncogene 19:2532-47 7592760 Pubmed 1995 Activation of the STAT3/acute phase response factor transcription factor by interleukin-5 Caldenhoven, E van Dijk, T Raaijmakers, JA Lammers, JW Koenderman, L de Groot, RP J Biol Chem 270:25778-84 9685210 Pubmed 1998 In vitro interaction between STAT 5 and JAK 2; dependence upon phosphorylation status of STAT 5 and JAK 2 Flores-Morales, A Pircher, TJ Silvennoinen, O Gustafsson, JA Sanchez-Gomez, M Norstedt, G Haldosén, LA Wood, TJ Mol Cell Endocrinol 138:1-10 7796299 Pubmed 1995 Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process Greenlund, AC Morales, MO Viviano, BL Yan, H Krolewski, J Schreiber, RD Immunity 2:677-87 15528381 Pubmed 2004 IL-5 and granulocyte-macrophage colony-stimulating factor activate STAT3 and STAT5 and promote Pim-1 and cyclin D3 protein expression in human eosinophils Stout, BA Bates, ME Liu, LY Farrington, NN Bertics, PJ J Immunol 173:6409-17 7539031 Pubmed 1995 Interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5 transduce signals through two forms of STAT5 Mui, AL Wakao, H Harada, N O'Farrell, AM Miyajima, A J Leukoc Biol 57:799-803 11458499 Pubmed 2001 Pathways in cytokine regulation of hematopoiesis Ihle, J Ann N Y Acad Sci 938:129-30 11122381 Pubmed 2000 In vitro analysis of STAT5 activation by granulocyte-macrophage colony-stimulating factor Sakurai, Y Arai, K Watanabe, S Genes Cells 5:937-947 9287210 Pubmed 1997 STATs and gene regulation Darnell JE, Jr Science 277:1630-5 inferred by electronic annotation IEA GO IEA 2.7.10.2 Activation of STAT5a/b by JAK2 Activation of STAT5a/b by JAK2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 6 Converted from EntitySet in Reactome Reactome DB_ID: 9852248 1 Reactome DB_ID: 29370 6 Converted from EntitySet in Reactome Reactome DB_ID: 9852254 1 High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2:p-STAT5 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9852248 GO 0004713 GO molecular function Reactome Database ID Release 82 9852255 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852255 Reactome Database ID Release 82 9852257 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852257 Reactome R-MMU-879909 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879909.1 JAK2 phosphorylates STAT5; phosphorylated STAT5 dimerizes and translocates to the nucleus (Darnell et al., 1994), binds DNA and activates target genes including c-fos, pim-1, oncostatin M, and Id-1 (Mui et al. 1996). STAT5 activation is believed to be the primary signaling mechanism for Bc (Ihle, 2001). 8197455 Pubmed 1994 Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins Darnell JE, Jr Kerr, IM Stark, GR Science 264:1415-21 8665850 Pubmed 1996 Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation Mui, AL Wakao, H Kinoshita, T Kitamura, T Miyajima, A EMBO J 15:2425-33 inferred by electronic annotation IEA GO IEA p-STAT5 dissociates from the receptor complex p-STAT5 dissociates from the receptor complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9852254 1 Converted from EntitySet in Reactome Reactome DB_ID: 9850277 3 p-STAT5A, p-STAT5B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Stat5b [cytosol] phospho-Stat5a [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 9852259 1 Reactome Database ID Release 82 9853749 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853749 Reactome R-MMU-921155 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-921155.1 Deletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believe to occur following the release of phosphorylated monomers (e.g. Turkson & Jove 2000). 11426647 Pubmed 2000 STAT proteins: novel molecular targets for cancer drug discovery Turkson, J Jove, R Oncogene 19:6613-26 9030599 Pubmed 1997 A single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activation Behrmann, I Janzen, C Gerhartz, C Schmitz-Van de Leur, H Hermanns, H Heesel, B Graeve, L Horn, F Tavernier, J Heinrich, PC J Biol Chem 272:5269-74 inferred by electronic annotation IEA GO IEA 2.7.10.2 Tyrosine kinases phosphorylate the receptor Tyrosine kinases phosphorylate the receptor This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9852225 1 Reactome DB_ID: 113592 12 Reactome DB_ID: 29370 12 Converted from EntitySet in Reactome Reactome DB_ID: 9852227 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)-Bc [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9852235 Tyrosine kinases that phosphorylate the Common beta chain [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 82 9852236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852236 Reactome Database ID Release 82 9852238 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852238 Reactome R-MMU-879907 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879907.1 Phosphorylation of the receptor common beta chain (Bc) creates binding sites for proteins that trigger subsequent signaling cascades (Pawson & Scott, 1997). The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One site is Y766 (numbered as Y750 by Sakamaki et al. 1992 and many other publications). Phosphorylation of Bc in response to GM-CSF/IL3 is observed at low temperatures (4 degrees C) that prevent the phosphorylation of other proteins, suggesting that the kinase responsible is likely to be physically associated with the receptor complex prior to stimulation (Miyajima et al. 1993). JAK2 is activated in response to IL-3, IL-5 and GM-CSF but signaling via JAK/STAT is not dependent on Bc tyrosine phosphorylation (Okuda et al. 1997). Based on these observations and the role of JAK1/3 in IL-2 signaling, JAK2 is believed to be the most likely candidate responsible for the phosphorylation of Bc (Guthridge et al. 1998). To represent the possible phosphorylation of Bc by kinases other than JAK2, this reaction includes receptor complexes with both active and inactive JAK2. Phosphorylation is represented only where this is necesssary for subsequent signaling; phosphorylation at other positions is probable. 8400249 Pubmed 1993 Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5 Miyajima, A Mui, AL Ogorochi, T Sakamaki, K Blood 82:1960-74 9405336 Pubmed 1997 Signaling through scaffold, anchoring, and adaptor proteins Pawson, T Scott, JD Science 278:2075-80 inferred by electronic annotation IEA GO IEA Recruitment of SHC1 is mediated by Y593 of the common beta chain Recruitment of SHC1 is mediated by Y593 of the common beta chain This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9852227 1 Reactome DB_ID: 9820615 3 UniProt:P98083-2 Shc1 Shc1 Shc1 ShcA Shc FUNCTION Signaling adapter that couples activated growth factor receptors to signaling pathways. Participates in signaling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis (By similarity). Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Isoform p47Shc and isoform p52Shc, once phosphorylated, couple activated receptor kinases to Ras via the recruitment of the GRB2/SOS complex and are implicated in the cytoplasmic propagation of mitogenic signals. Isoform p47Shc and isoform p52 may thus function as initiators of the Ras signaling cascade in various non-neuronal systems. Isoform p66Shc does not mediate Ras activation, but is involved in signal transduction pathways that regulate the cellular response to oxidative stress and life span. Isoform p66Shc acts as a downstream target of the tumor suppressor p53 and is indispensable for the ability of stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release and apoptosis. The expression of isoform p66Shc has been correlated with life span.SUBUNIT Interacts with CPNE3; this interaction may mediate the binding of CPNE3 with ERBB2 (By similarity). Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR in vitro via the PID domain. Once activated, binds to GRB2. Interacts with tyrosine-phosphorylated DDR2 and CD3T. Interacts with the N-terminal region of APS. Interacts with GRB7 and KIT (By similarity). Interacts with PTK2/FAK1 (By similarity). Interacts with phosphorylated LRP1 and IRS4. Interacts with FLT4 (tyrosine-phosphorylated) (By similarity). Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with ERBB4 (By similarity). Interacts with TEK/TIE2 (tyrosine-phosphorylated) (By similarity). Interacts with ALK, GAB2, TRIM31, INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with PTPN6/SHP (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Interacts with EPHB1 and GRB2; activates the MAPK/ERK cascade to regulate cell migration. Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a phosphotyrosine-dependent manner. Interacts with CEACAM1; this interaction is CEACAM1-phosphorylation-dependent and mediates interaction with EGFR or INSR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (By similarity) (PubMed:15467833). Interacts (via PID domain) with PEAK1 (when phosphorylated at 'Tyr-1177') (By similarity). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (By similarity).TISSUE SPECIFICITY Widely expressed. Expressed in neural stem cells but absent in mature neurons.DOMAIN In response to a variety of growth factors, isoform p47Shc and isoform p52 bind to phosphorylated receptors through their phosphotyrosine binding (PID) and/or SH2 domains. The PID and SH2 domains bind to specific phosphorylated tyrosine residues in the Asn-Pro-Xaa-Tyr(P) motif. Isoform p47Shc and isoform p52Shc are in turn phosphorylated on three tyrosine residues within the extended proline-rich domain. These phosphotyrosines act as docking site for GRB2 and thereby are involved in Ras activation.PTM Phosphorylated in response to FLT4 signaling (By similarity). Tyrosine phosphorylated by ligand-activated PDGFRB (By similarity). May be tyrosine phosphorylated by activated PTK2/FAK1 (By similarity). Tyrosine phosphorylated by TEK/TIE2 (By similarity). Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity). Dephosphorylation by PTPN2 may regulate interaction with GRB2 (By similarity). Phosphorylated by activated epidermal growth factor receptor. Phosphorylated in response to KIT signaling. Isoform p47Shc and isoform p52Shc are phosphorylated on tyrosine residues of the Pro-rich domain. Isoform p66Shc is phosphorylated on Ser-36 by PRKCB upon treatment with insulin, hydrogen peroxide or irradiation with ultraviolet light. FLT3 signaling promotes tyrosine phosphorylation of isoform p47Shc and isoform p52Shc. Also tyrosine phosphorylated by ligand-activated ALK. UniProt P98083-2 Chain Coordinates 1 EQUAL 583 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9852281 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)-Bc:SHC1 [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 82 9852285 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852285 Reactome R-MMU-879934 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879934.1 Upon receptor activation, Shc is recruited to the receptor complex, where it becomes tyrosine phosphorylated. The recruitment of Shc is mediated by Y593 (Y577 in the mature peptide) of the common beta chain (Bc), which binds the PTB domain of Shc (Pratt et al. 1996). Phosphorylated Shc interacts with Grb2 within a Grb2:Gab2 complex, promoting tyrosine phosphorylation of Gab2. The p85 subunit of PI3Kinases associates with phosphorylated Gab, and this induces activation of the catalytic p110 PI3K subunit leading to activation of Akt kinase, thereby regulating cell survival and/or proliferation. 10982827 Pubmed 2000 New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway Gu, H Maeda, H Moon, JJ Lord, JD Yoakim, M Nelson, BH Neel, BG Mol Cell Biol 20:7109-20 inferred by electronic annotation IEA GO IEA Interleukin receptor SHC signaling Interleukin receptor SHC signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Phosphorylated SHC1 recruits GRB2:GAB2 Phosphorylated SHC1 recruits GRB2:GAB2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9850340 1 Interleukin receptor complexes with activated SHC1 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 9850342 4 GRB2:GAB2 [cytosol] GRB2:GAB2 Reactome DB_ID: 9837172 1 UniProt:Q9Z1S8 Gab2 Gab2 Gab2 FUNCTION Adapter protein which acts downstream of several membrane receptors including cytokine, antigen, hormone, cell matrix and growth factor receptors to regulate multiple signaling pathways. Regulates osteoclast differentiation mediating the TNFRSF11A/RANK signaling. In allergic response, it plays a role in mast cells activation and degranulation through PI-3-kinase regulation. Also involved in the regulation of cell proliferation and hematopoiesis.SUBUNIT Interacts with HCK (By similarity). Interacts with SHC1; may mediate interaction with receptors. Interacts with SYK. Interacts with PI-3 kinase. Interacts with GRB2 (via SH3 2 domain). Interacts (phosphorylated) with PTPN11. Interacts with TNFRSF11A (via cytoplasmic domain). Interacts (phosphorylated) with 14-3-3 family proteins SFN, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ; prevents interaction with GRB2 and attenuates GAB2 signaling.TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN The SH3-binding motifs mediate interaction with SHC1 and GRB2.DOMAIN The PH domain mediates phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate binding.PTM Phosphorylated upon EGF stimulation. Phosphorylated on tyrosine residues by HCK upon IL6 signaling (By similarity). Phosphorylated on tyrosine residue(s) by the thrombopoietin receptor (TPOR), stem cell factor receptor (SCFR), and T-cell and B-cell antigen receptors, gp130, IL-2R and IL-3R. Phosphorylated upon stimulation of TNFRSF11A/RANK by TNFSF11/RANKL.PTM Dephosphorylated by PTPN11.DISRUPTION PHENOTYPE Mice are viable and healthy for up to 15 months. However, they have reduced number of mast cells and develop osteopetrosis.SIMILARITY Belongs to the GAB family. UniProt Q9Z1S8 1 EQUAL 676 EQUAL Reactome DB_ID: 9029108 1 UniProt:Q60631-1 Grb2 Grb2 Grb2 FUNCTION Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.SUBUNIT Associates (via SH2 domain) with activated EGF and PDGF receptors (tyrosine phosphorylated) (By similarity). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect (PubMed:8943348). Interacts with IRS4 (when Tyr-phosphorylated) (PubMed:11113178). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, IRS1, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains (By similarity). It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1 (By similarity). Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1 (By similarity). Interacts with phosphorylated MET (By similarity). Interacts with phosphorylated TOM1L1 (PubMed:11711534). Interacts with the phosphorylated C-terminus of SH2B2 (By similarity). Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation (By similarity) (PubMed:16249387, PubMed:14610044, PubMed:15477350, PubMed:15477348, PubMed:22561606). Interacts with NISCH, PTPNS1 and REPS2 (By similarity). Interacts with syntrophin SNTA1 (PubMed:11551227). Interacts (via SH3 domains) with REPS1 (PubMed:9395447). Interacts (via SH3 domains) with PIK3C2B (By similarity). Interacts with CBL and CBLB (By similarity). Interacts with AJUBA and CLNK (PubMed:10330178, PubMed:11463797). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (PubMed:10521483). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2 (By similarity). Interacts with PTPN11 (PubMed:8943348). Interacts with PRNP (PubMed:11571277). Interacts with RALGPS1 (By similarity). Interacts also with HCST (PubMed:16582911). Interacts with KDR (PubMed:16966330). Interacts with FLT1 (tyrosine-phosphorylated) (PubMed:9722576). Interacts with GAPT and PTPRE (By similarity). Interacts (via SH2 domain) with KIF26A (By similarity). Interacts (via SH3 2) with GAB2 (PubMed:10068651). Interacts with ADAM15 (By similarity). Interacts with THEMIS2 (PubMed:20644716). Interacts (via SH2 domain) with AXL (phosphorylated) (By similarity). Interacts (via SH2 domain) with KIT (phosphorylated) (PubMed:10377264). Interacts with PTPRJ and BCR (By similarity). Interacts with PTPN23 (By similarity). Interacts with FLT4 (tyrosine phosphorylated) (By similarity). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Part of a complex including TNK2, GRB2 and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2 (By similarity). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:9312046). Interacts with ERBB4 (By similarity). Interacts with NTRK1 (phosphorylated upon ligand-binding) (By similarity). Interacts with PTK2/FAK1 (tyrosine phosphorylated) (PubMed:7997267). Interacts with PTK2B/PYK2 (tyrosine phosphorylated) (By similarity). Interacts (via SH2-domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-58' (PubMed:21930792, PubMed:28098138, PubMed:28290451). Interacts (via SH3 domains) with GAREM1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation (By similarity). Interacts with DAB2 (PubMed:9569023). Interacts with TESPA1 (By similarity). Interacts with THEMIS (PubMed:19597498, PubMed:19597497, PubMed:19805304, PubMed:22561606). Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1 (PubMed:22561606). Interacts with CD28 (By similarity). Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA (PubMed:21543326). Interacts with ASAP3 (phosphorylated form) (By similarity). Interacts (via SH2 domain) with PTPRH (phosphorylated form) (PubMed:20398064). Interacts with PTPRO (phosphorylated form) (PubMed:20398064). Interacts with PTPRB (phosphorylated form) (PubMed:20398064). Interacts (via SH3 domain 2) with PRR14 (via proline-rich region) (By similarity). Interacts with DENND2B (By similarity). Interacts with SPRY2 (By similarity). Interacts with LRRC8A (PubMed:32930093).TISSUE SPECIFICITY Expressed in macrophages.DOMAIN The SH3 domains mediate interaction with RALGPS1 and SHB.SIMILARITY Belongs to the GRB2/sem-5/DRK family. UniProt Q60631-1 1 EQUAL 217 EQUAL Reactome Database ID Release 82 9850342 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850342 Reactome R-MMU-912522 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912522.1 Converted from EntitySet in Reactome Reactome DB_ID: 9850352 1 Interleukin receptor compexes with activated Shc:GRB2:GAB2 [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 82 9850354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850354 Reactome R-MMU-453104 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-453104.1 Phosphorylated Shc recruits Grb2 and Gab2, probably by binding to Grb2 in the Grb2:Gab2 complex. Gab2 associates with Grb2, Shc, Shp2 and the p85 subunit of PI3K (Gu et al. 1998). The association of Grb2 with Gab2 has been suggested to be constitutive (Gu et al. 2000, Kong et al. 2003, Harkiolaki et al. 2009), so Gab2 may be recruited to Shc1 with Grb2. Alternatively, Gab2 has been suggested to associate constitutively with Shc (Kong et al 2003). In either case, the result is a complex of Shc:Grb2:Gab2. Gab2 binding to p85 (Gu et al. 1998) links Shc1 to PI3K activity and subsequent activation of kinases such as Akt (Gu et al. 2000). 9885561 Pubmed 1998 Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation Gu, H Pratt, JC Burakoff, SJ Neel, BG Mol Cell 2:729-40 12464621 Pubmed 2003 Epidermal growth factor-induced DNA synthesis. Key role for Src phosphorylation of the docking protein Gab2 Kong, M Mounier, C Dumas, V Posner, BI J Biol Chem 278:5837-44 19523899 Pubmed 2009 Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2 Harkiolaki, M Tsirka, T Lewitzky, M Simister, PC Joshi, D Bird, LE Jones, EY O'Reilly, N Feller, SM Structure 17:809-22 8084588 Pubmed 1994 Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins Salcini, AE McGlade, J Pelicci, G Nicoletti, I Pawson, T Pelicci, PG Oncogene 9:2827-36 inferred by electronic annotation IEA GO IEA SHC1 mediates cytokine-induced phosphorylation of GAB2 SHC1 mediates cytokine-induced phosphorylation of GAB2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 4 Converted from EntitySet in Reactome Reactome DB_ID: 9850352 1 Reactome DB_ID: 29370 4 Converted from EntitySet in Reactome Reactome DB_ID: 9851219 1 Interleukin receptor complexes with activated Shc:GRB2:p-GAB2 [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 82 9852667 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852667 Reactome R-MMU-912527 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912527.1 Binding of Gab2 to tyrosine phosphorylated Shc promotes the phosphorylation of Gab2 by an unknown kinase. Gab2 becomes tyrosine phosphorylated in response to IL-2 (Brockdorff et al. 2001) and IL-3 (Gu et al. 1998). Chimeric receptors were used to demonstrate that Shc is sufficient for Gab2 tyrosine phosphorylation. In response to IL-3, Grb2 was also required, reflecting that Gab2 is recruited to the activated cytokine receptor complex as a complex of Gab2:Grb2 (Gu et al. 2000). 11340297 Pubmed 2001 Gab2 is phosphorylated on tyrosine upon interleukin-2/interleukin-15 stimulation in mycosis-fungoides-derived tumor T cells and associates inducibly with SHP-2 and Stat5a Brockdorff, JL Gu, H Mustelin, T Kaltoft, K Geisler, C Röpke, C Ødum, N Exp Clin Immunogenet 18:86-95 inferred by electronic annotation IEA GO IEA Gab2 binds the p85 subunit of Class 1A PI3 kinases Gab2 binds the p85 subunit of Class 1A PI3 kinases This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9851207 4 p85-containing Class 1A PI3Ks [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 9851219 1 Converted from EntitySet in Reactome Reactome DB_ID: 9851237 1 Interleukin receptor complexes with activated Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Ks [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 82 9851239 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9851239 Reactome R-MMU-508247 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-508247.1 Shc promotes Gab2 tyrosine phosphorylation via Grb2 (Gu et al. 2000). This promotes binding of Gab2 to p85alpha, a component of Class 1A PI3Ks (Gu et al. 1998). JAK1 may also be involved in PI3K recruitment (Migone et al. 1998). Binding of p85 activates PI3K kinase activity, with consequent effects on many processes including Akt activation. This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors, the other is mediated by Serine-585 phosphorylation of the common beta chain. 9774657 Pubmed 1998 Functional cooperation of the interleukin-2 receptor beta chain and Jak1 in phosphatidylinositol 3-kinase recruitment and phosphorylation Migone, TS Rodig, S Cacalano, NA Berg, M Schreiber, RD Leonard, WJ Mol Cell Biol 18:6416-22 10455108 Pubmed 1999 Engagement of Gab1 and Gab2 in erythropoietin signaling Wickrema, A Uddin, S Sharma, A Chen, F Alsayed, Y Ahmad, S Sawyer, ST Krystal, G Yi, T Nishada, K Hibi, M Hirano, T Platanias, LC J Biol Chem 274:24469-74 inferred by electronic annotation IEA GO IEA Phosphorylated SHC recruits GRB2:SOS1 Phosphorylated SHC recruits GRB2:SOS1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9820588 4 GRB2-1:SOS1 [cytosol] GRB2-1:SOS1 Reactome DB_ID: 9820586 1 UniProt:Q62245 Sos1 Sos1 Sos1 FUNCTION Promotes the exchange of Ras-bound GDP by GTP. Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (By similarity). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity (PubMed:10499589, PubMed:11524436).SUBUNIT Interacts (via C-terminus) with GRB2 (via SH3 domain). Forms a complex with phosphorylated MUC1 and GRB2 (via its SH3 domains). Interacts with phosphorylated LAT2. Interacts with NCK1 and NCK2 (By similarity). Part of a complex consisting of ABI1, EPS8 and SOS1 (PubMed:10499589, PubMed:11524436). Interacts (Ser-1120 and Ser-1147 phosphorylated form) with YWHAB and YWHAE (By similarity).TISSUE SPECIFICITY Expressed in most embryonic and adult tissues.PTM Phosphorylation at Ser-1120 and Ser-1147 by RPS6KA3 create YWHAB and YWHAE binding sites and which contribute to the negative regulation of EGF-induced MAPK1/3 phosphorylation. UniProt Q62245 1 EQUAL 1333 EQUAL Reactome DB_ID: 9029108 1 1 EQUAL 217 EQUAL Reactome Database ID Release 82 9820588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9820588 Reactome R-MMU-109797 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-109797.1 Converted from EntitySet in Reactome Reactome DB_ID: 9850340 1 Reactome DB_ID: 9850356 1 Interleukin receptor complexes with activated SHC1:GRB2:SOS1 [plasma membrane] Interleukin receptor complexes with activated SHC1:GRB2:SOS1 Reactome DB_ID: 9820588 4 Converted from EntitySet in Reactome Reactome DB_ID: 9850340 1 Reactome Database ID Release 82 9850356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850356 Reactome R-MMU-921157 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-921157.1 Reactome Database ID Release 82 9850358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9850358 Reactome R-MMU-453111 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-453111.1 Shc is tyrosine phosphorylated by an unidentified kinase, creating a docking site for the SH2 domain of Grb2 (Zhu et al. 1994). Grb2 is an adaptor protein believed to be constitutively associated with the guanine nucleotide exchange protein Sos1 (often abbreviated to Sos). Recruitment of the Grb2:Sos1 complex leads to activation of the Ras pathway (Ravichandran & Burakoff 1994) and consequently activation of the MAPK pathway. 8119884 Pubmed 1994 Interleukin-2-induced tyrosine phosphorylation of Shc proteins correlates with factor-dependent T cell proliferation Zhu, X Suen, KL Barbacid, M Bolen, JB Fargnoli, J J Biol Chem 269:5518-22 1465135 Pubmed 1992 Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases Rozakis-Adcock, M McGlade, J Mbamalu, G Pelicci, G Daly, R Li, W Batzer, A Thomas, S Brugge, J Pelicci, PG Nature 360:689-92 8294403 Pubmed 1994 The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation Ravichandran, KS Burakoff, SJ J Biol Chem 269:1599-602 inferred by electronic annotation IEA GO IEA Phosphorylated SHC1 recruits SHIP Phosphorylated SHC1 recruits SHIP This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9850340 1 Converted from EntitySet in Reactome Reactome DB_ID: 9852788 4 SHIP1,2 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Inpp5d [cytosol] Inppl1 [cytosol] UniProt Q9ES52 UniProt Q6P549 Reactome DB_ID: 9852790 1 Interleukin receptor complexes with activated SHC1:SHIP1,2 [plasma membrane] Interleukin receptor complexes with activated SHC1:SHIP1,2 Converted from EntitySet in Reactome Reactome DB_ID: 9850340 1 Converted from EntitySet in Reactome Reactome DB_ID: 9852788 4 Reactome Database ID Release 82 9852790 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852790 Reactome R-MMU-913393 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-913393.1 Reactome Database ID Release 82 9852792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852792 Reactome R-MMU-913374 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-913374.1 SHIP dephosphorylates PIP3 and may limit the magnitude or duration of signaling events that are dependent upon PIP3-mediated membrane recruitment of plextrin homology (PH) domain signalling proteins such as PI3K and Akt (Aman et al. 1998). The PTB domain of SHC1 binds to phosphorylated tyrosine residues on SHIP. Mutations that inactivate the PTB domain prevent this binding and substitution of F for Y917 and Y1020 on SHIP prevents creation of the phosphotyrosine motifs that are recognized by the SHC1 PTB domain, blocking the interaction (Lamkin et al. 1997). A functional SHIP SH2 domain is also reported as a requirement for association of SHIP with Shc (Liu et al. 1997). GRB2 stabilizes the SHC1/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on SHC1, forming a ternary complex of SHC1:GRB2:SHIP described as inducible by IL-3, IL-5 or GM-CSF by many authors (Jucker et al. 1997, Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999). 10194451 Pubmed 1999 A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells Wisniewski, Douglas Strife, A Swendeman, S Erdjument-Bromage, H Geromanos, S Kavanaugh, WM Tempst, P Clarkson, B Blood 93:2707-20 9108392 Pubmed 1997 Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl Odai, H Sasaki, K Iwamatsu, A Nakamoto, T Ueno, H Yamagata, T Mitani, K Yazaki, Y Hirai, H Blood 89:2745-56 9083021 Pubmed 1997 The Src homology 2 (SH2) domain of SH2-containing inositol phosphatase (SHIP) is essential for tyrosine phosphorylation of SHIP, its association with Shc, and its induction of apoptosis Liu, L Damen, JE Hughes, MR Babic, I Jirik, FR Krystal, G J Biol Chem 272:8983-8 9058724 Pubmed 1997 A tyrosine-phosphorylated protein of 140 kD is constitutively associated with the phosphotyrosine binding domain of Shc and the SH3 domains of Grb2 in acute myeloid leukemia cells Jücker, M Schiffer, CA Feldman, RA Blood 89:2024-35 10570274 Pubmed 1999 Tyrosine phosphorylation of shc in response to B cell antigen receptor engagement depends on the SHIP inositol phosphatase Ingham, RJ Okada, H Dang-Lawson, M Dinglasan, J van der Geer, P Kurosaki, T Gold, MR J Immunol 163:5891-5 10207047 Pubmed 1999 The src homology domain 2-containing inositol phosphatase SHIP forms a ternary complex with Shc and Grb2 in antigen receptor-stimulated B lymphocytes Harmer, SL DeFranco, AL J Biol Chem 274:12183-91 9852043 Pubmed 1998 The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells Aman, MJ Lamkin, TD Okada, H Kurosaki, T Ravichandran, KS J Biol Chem 273:33922-8 9099679 Pubmed 1997 Shc interaction with Src homology 2 domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP Lamkin, TD Walk, SF Liu, L Damen, JE Krystal, G Ravichandran, KS J Biol Chem 272:10396-401 7898932 Pubmed 1995 Overexpression of Shc proteins potentiates the proliferative response to the granulocyte-macrophage colony-stimulating factor and recruitment of Grb2/SoS and Grb2/p140 complexes to the beta receptor subunit Lanfrancone, L Pelicci, G Brizzi, MF Aronica, MG Casciari, C Giuli, S Pegoraro, L Pawson, T Pelicci, PG Arouica, MG Oncogene 10:907-17 inferred by electronic annotation IEA GO IEA The SHC1:SHIP1 complex is stabilized by GRB2 The SHC1:SHIP1 complex is stabilized by GRB2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9029108 4 1 EQUAL 217 EQUAL Reactome DB_ID: 9852794 1 Interleukin receptor complexes with activated SHC1:SHIP1 [plasma membrane] Interleukin receptor complexes with activated SHC1:SHIP1 Converted from EntitySet in Reactome Reactome DB_ID: 9850340 1 Reactome DB_ID: 9837225 4 UniProt:P29351 Ptpn6 Ptpn6 Hcph Ptp1C Hcp Ptpn6 FUNCTION Modulates signaling by tyrosine phosphorylated cell surface receptors such as KIT and the EGF receptor/EGFR. Enhances the inhibition of mast cell activation mediated by the Lilrb4a receptor (PubMed:10026201). The SH2 regions may interact with other cellular components to modulate its own phosphatase activity against interacting substrates. Together with MTUS1, induces UBE2V2 expression upon angiotensin II stimulation. Plays a key role in hematopoiesis.SUBUNIT Monomer. Interacts with MTUS1 (By similarity). Interacts with MILR1 (tyrosine-phosphorylated) (PubMed:20526344). Interacts with KIT (PubMed:9528781). Interacts with SIRPA/PTPNS1 (PubMed:9712903). Interacts with FCRL2 and FCRL4 (By similarity). Interacts with CD84 (By similarity). Interacts with CD300LF (PubMed:14662855). Interacts with CDK2 (By similarity). Interacts with KIR2DL1; the interaction is enhanced by ARRB2 (By similarity). Interacts (via SH2 1 domain) with ROS1; the interaction is direct and promotes ROS1 dephosphorylation (By similarity). Interacts with EGFR; inhibits EGFR-dependent activation of MAPK/ERK (By similarity). Interacts with LYN (By similarity). Interacts with the tyrosine phosphorylated form of PDPK1 (By similarity). Interacts with CEACAM1 (via cytoplasmic domain); this interaction depends on the monomer/dimer equilibrium and is phosphorylation-dependent (PubMed:19948503, PubMed:9867848). Interacts with MPIG6B (via ITIM motif) (PubMed:23112346). Interacts with KLRI1 and KLRI2 (By similarity). Interacts with moesin/MSN. Interacts with Lilrb4a (when tyrosine phosphorylated); the interaction enhances Lilrb4a-mediated inhibition of mast cell activation (PubMed:10026201, PubMed:9973385). Interacts with CLEC12B (via ITIM motif).TISSUE SPECIFICITY Expressed predominantly in hematopoietic cells.DOMAIN The N-terminal SH2 domain functions as an auto-inhibitory domain, blocking the catalytic domain in the ligand-free close conformation.PTM Phosphorylated on tyrosine residues. Phosphorylation at Tyr-564 enhances phosphatase activity (By similarity). Binding of KITLG/SCF to KIT increases tyrosine phosphorylation.DISEASE Defects in Ptpn6 are the cause of the motheaten (me) or viable motheaten (mev) phenotypes. Mice homozygous for the recessive allelic mutations develop severe defects in hematopoiesis.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily. UniProt P29351 1 EQUAL 595 EQUAL Reactome Database ID Release 82 9852794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852794 Reactome R-MMU-913378 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-913378.1 Reactome DB_ID: 9852796 1 Interleukin receptor complexes with activated SHC1:SHIP:GRB2 [plasma membrane] Interleukin receptor complexes with activated SHC1:SHIP:GRB2 Reactome DB_ID: 9029108 4 1 EQUAL 217 EQUAL Reactome DB_ID: 9852794 1 Reactome Database ID Release 82 9852796 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852796 Reactome R-MMU-913411 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-913411.1 Reactome Database ID Release 82 9852798 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852798 Reactome R-MMU-913424 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-913424.1 Grb2 stabilizes the Shc/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on Shc. This forms a ternary complex of SHC1:GRB2:SHIP described as an outcome of IL-3, IL-5 or GM-CSF stimulation (Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 9927154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9927154 Reactome R-MMU-912526 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912526.1 Phosphorylation of Shc at three tyrosine residues, 239, 240 (Gotoh et al. 1996) and 317 (Salcini et al. 1994) involves unidentified tyrosine kinases presumed to be part of the activated receptor complex. These phosphorylated tyrosines subsequently bind SH2 signaling proteins such as Grb2, Gab2 and SHIP that are involved in the regulation of different signaling pathways. Grb2 can associate with the guanosine diphosphate-guanosine triphosphate exchange factor Sos1, leading to Ras activation and regulation of cell proliferation. Downstream signals are mediated via the Raf-MEK-Erk pathway.Grb2 can also associate through Gab2 with PI3K and with SHIP.<br><br>Figure reproduced from Gu, H. et al. 2000. Mol. Cell. Biol. 20(19):7109-7120<br>Copyright American Society for Microbiology. All Rights Reserved. 8947042 Pubmed 1996 A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL-3 Gotoh, N Tojo, A Shibuya, M EMBO J 15:6197-204 inferred by electronic annotation IEA GO IEA Regulation of signaling by CBL Regulation of signaling by CBL This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> CBL, GRB2, FYN and PI3K p85 subunit are constitutively associated CBL, GRB2, FYN and PI3K p85 subunit are constitutively associated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9852271 1 FYN-like kinases [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Fyn [cytosol] UniProt P39688 Converted from EntitySet in Reactome Reactome DB_ID: 9851207 1 Reactome DB_ID: 9029108 1 1 EQUAL 217 EQUAL Reactome DB_ID: 9830853 1 UniProt:P22682 UniProt P22682 1 EQUAL 906 EQUAL Reactome DB_ID: 9852273 1 FYN-like kinases:CBL:GRB2:p85-containing Class 1A PI3Ks [cytosol] FYN-like kinases:CBL:GRB2:p85-containing Class 1A PI3Ks Converted from EntitySet in Reactome Reactome DB_ID: 9852271 1 Converted from EntitySet in Reactome Reactome DB_ID: 9851207 1 Reactome DB_ID: 9029108 1 1 EQUAL 217 EQUAL Reactome DB_ID: 9830853 1 1 EQUAL 906 EQUAL Reactome Database ID Release 82 9852273 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852273 Reactome R-MMU-912623 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912623.1 Reactome Database ID Release 82 9852275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852275 Reactome R-MMU-879917 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879917.1 Cbl is constitutively associated with Grb2 in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain can bind the adaptor protein CRKL.<br><br> Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998). <br>Cbl also associates with Fyn (Anderson et al. 1997) and the related kinases Hck and Lyn (Hunter et al. 1999). Binding studies indicate that this binding is independent of the phosphorylation state of Cbl; The association of Fyn with Cbl has been described as constitutive (Hunter et al. 1999).<br><br> Cbl further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this is also described as constitutive and is mediated by the SH3 domain of p85 (Hunter et al. 1997). 9890970 Pubmed 1999 Fyn associates with Cbl and phosphorylates tyrosine 731 in Cbl, a binding site for phosphatidylinositol 3-kinase Hunter, S Burton, EA Wu, SC Anderson, SM J Biol Chem 274:2097-106 7629144 Pubmed 1995 Specific association of the beta isoform of the p85 subunit of phosphatidylinositol-3 kinase with the proto-oncogene c-cbl Hartley, D Meisner, H Corvera, S J Biol Chem 270:18260-3 9259313 Pubmed 1997 Phosphorylation of cbl after stimulation of Nb2 cells with prolactin and its association with phosphatidylinositol 3-kinase Hunter, S Koch, BL Anderson, SM Mol Endocrinol 11:1213-22 9590251 Pubmed 1998 CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling Park, RK Kyono, WT Liu, Y Durden, DL J Immunol 160:5018-27 7537740 Pubmed 1995 The proto-oncogene product c-Cbl becomes tyrosine phosphorylated by stimulation with GM-CSF or Epo and constitutively binds to the SH3 domain of Grb2/Ash in human hematopoietic cells Odai, H Sasaki, K Iwamatsu, A Hanazono, Y Tanaka, T Mitani, K Yazaki, Y Hirai, H J Biol Chem 270:10800-5 8995358 Pubmed 1997 Phosphorylation of Cbl following stimulation with interleukin-3 and its association with Grb2, Fyn, and phosphatidylinositol 3-kinase Anderson, SM Burton, EA Koch, BL J Biol Chem 272:739-45 8621719 Pubmed 1996 p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinases, Grb2 and Shc adaptors, and the p85 subunit of phosphatidylinositol 3-kinase Panchamoorthy, G Fukazawa, T Miyake, S Soltoff, S Reedquist, K Druker, B Shoelson, S Cantley, Lewis C Band, H J Biol Chem 271:3187-94 inferred by electronic annotation IEA GO IEA CBL ubiquitinates PI3K CBL ubiquitinates PI3K This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9852674 1 FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3Ks [cytosol] FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3Ks Converted from EntitySet in Reactome Reactome DB_ID: 9852271 1 Converted from EntitySet in Reactome Reactome DB_ID: 9851207 1 Reactome DB_ID: 9029108 1 1 EQUAL 217 EQUAL Reactome DB_ID: 9852672 1 O4'-phospho-L-tyrosine at 731 (in Homo sapiens) 731 EQUAL O4'-phospho-L-tyrosine [MOD:00048] O4'-phospho-L-tyrosine at 700 (in Homo sapiens) 700 EQUAL O4'-phospho-L-tyrosine at 774 (in Homo sapiens) 774 EQUAL 1 EQUAL 906 EQUAL Reactome Database ID Release 82 9852674 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852674 Reactome R-MMU-912647 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912647.1 Reactome DB_ID: 9852720 1 K48polyUb [cytosol] K48polyUb Reactome DB_ID: 9852741 1 FYN-like kinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3Ks [cytosol] FYN-like kinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3Ks Converted from EntitySet in Reactome Reactome DB_ID: 9852271 1 Converted from EntitySet in Reactome Reactome DB_ID: 9852739 1 K63polyUb-p85-containing Class 1A PI3Ks [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 9029108 1 1 EQUAL 217 EQUAL Reactome DB_ID: 9852672 1 O4'-phospho-L-tyrosine at 731 (in Homo sapiens) 731 EQUAL O4'-phospho-L-tyrosine at 700 (in Homo sapiens) 700 EQUAL O4'-phospho-L-tyrosine at 774 (in Homo sapiens) 774 EQUAL 1 EQUAL 906 EQUAL Reactome Database ID Release 82 9852741 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852741 Reactome R-MMU-912799 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912799.1 Reactome Database ID Release 82 9852743 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852743 Reactome R-MMU-912627 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912627.1 Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl-B targets PI3K for ubiquitination and degradation in T cells (Fang et al. 2000). Similarly, Cbl activation by tyrosine phosphorylation increases PI3K ubiquitination and proteasomal degradation (Dufour et al. 2008). 18374639 Pubmed 2008 FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival Dufour, C Guenou, H Kaabeche, K Bouvard, D Sanjay, A Marie, PJ Bone 42:1032-9 11087752 Pubmed 2001 Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells Fang, D Wang, HY Fang, N Altman, Y Elly, C Liu, YC J Biol Chem 276:4872-8 11994499 Pubmed 2002 The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system Rao, N Dodge, I Band, H J Leukoc Biol 71:753-63 inferred by electronic annotation IEA GO IEA CBL binds CRK CBL binds CRK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9843434 1 CRK, CRKL [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Crkl [cytosol] Crk [cytosol] UniProt P47941 UniProt Q64010 Reactome DB_ID: 9852672 1 O4'-phospho-L-tyrosine at 731 (in Homo sapiens) 731 EQUAL O4'-phospho-L-tyrosine at 700 (in Homo sapiens) 700 EQUAL O4'-phospho-L-tyrosine at 774 (in Homo sapiens) 774 EQUAL 1 EQUAL 906 EQUAL Reactome DB_ID: 9852757 1 p(Y700,731,774)-CBL:CRK [cytosol] p(Y700,731,774)-CBL:CRK Converted from EntitySet in Reactome Reactome DB_ID: 9843434 1 Reactome DB_ID: 9852672 1 O4'-phospho-L-tyrosine at 731 (in Homo sapiens) 731 EQUAL O4'-phospho-L-tyrosine at 700 (in Homo sapiens) 700 EQUAL O4'-phospho-L-tyrosine at 774 (in Homo sapiens) 774 EQUAL 1 EQUAL 906 EQUAL Reactome Database ID Release 82 9852757 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852757 Reactome R-MMU-912774 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912774.1 Reactome Database ID Release 82 9852782 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852782 Reactome R-MMU-912790 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912790.1 The Crk adapter protein family is comprised of Crk-I and Crk-II, alternatively spliced products of a single gene with differing biological functions, and Crk-L, a distinct Crk-like gene product. Cbl is the dominant phosphoprotein associated with Crk in activated lymphocytes. In vitro binding indicates that the Crk SH2 domain binds Y774 of Cbl (Reedquist et al. 1996), leaving the SH3 domain of Crk free to interact with other SH3 domain-associated proteins. 8649859 Pubmed 1996 The two major sites of cbl tyrosine phosphorylation in abl-transformed cells select the crkL SH2 domain Andoniou, CE Thien, CB Langdon, WY Oncogene 12:1981-9 8626543 Pubmed 1996 Stimulation through the T cell receptor induces Cbl association with Crk proteins and the guanine nucleotide exchange protein C3G Reedquist, KA Fukazawa, T Panchamoorthy, G Langdon, WY Shoelson, SE Druker, BJ Band, H J Biol Chem 271:8435-42 inferred by electronic annotation IEA GO IEA CBL:CRKL binds RAPGEF1 CBL:CRKL binds RAPGEF1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9852757 1 Reactome DB_ID: 9829174 1 UniProt:Q3UHC1 Rapgef1 Rapgef1 UniProt Q3UHC1 1 EQUAL 1077 EQUAL Reactome DB_ID: 9852759 1 p(Y700,731,774)-CBL:CRK:RAPGEF1 [cytosol] p(Y700,731,774)-CBL:CRK:RAPGEF1 Reactome DB_ID: 9852757 1 Reactome DB_ID: 9829174 1 1 EQUAL 1077 EQUAL Reactome Database ID Release 82 9852759 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852759 Reactome R-MMU-914209 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-914209.1 Reactome Database ID Release 82 9852761 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852761 Reactome R-MMU-912734 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912734.1 Cbl has been identified in ternary complexes with CRKL and C3G (RAPGEF1)(Reedquist et al. 1996) a Rap1 GEF, suggesting a role for Cbl in linking cytokine stimulation to Rap1 activation. Consistent with this, stimulation of NB-4 promyelocytic cells by IFN-gamma causes tyrosine phosphorylation and association of Cbl with CRKL followed by activation of Rap1 (Alsayed et al. 2000) and tyrosine phosphorylation of Cbl and its association with CRKL correlated with an increase in Rap 1 activity in anergic T cells (Boussiotis et al. 1997). 9311917 Pubmed 1997 Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1 Boussiotis, VA Freeman, GJ Berezovskaya, A Barber, DL Nadler, LM Science 278:124-8 10657627 Pubmed 2000 IFN-gamma activates the C3G/Rap1 signaling pathway Alsayed, Y Uddin, S Ahmad, S Majchrzak, B Druker, BJ Fish, EN Platanias, LC J Immunol 164:1800-6 inferred by electronic annotation IEA GO IEA CBL binds VAV CBL binds VAV This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 434625 1 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 1 EQUAL 845 EQUAL Reactome DB_ID: 9852672 1 O4'-phospho-L-tyrosine at 731 (in Homo sapiens) 731 EQUAL O4'-phospho-L-tyrosine at 700 (in Homo sapiens) 700 EQUAL O4'-phospho-L-tyrosine at 774 (in Homo sapiens) 774 EQUAL 1 EQUAL 906 EQUAL Reactome DB_ID: 9852753 1 p(Y700,731,774)-CBL:VAV1 [cytosol] p(Y700,731,774)-CBL:VAV1 Reactome DB_ID: 434625 1 1 EQUAL 845 EQUAL Reactome DB_ID: 9852672 1 O4'-phospho-L-tyrosine at 731 (in Homo sapiens) 731 EQUAL O4'-phospho-L-tyrosine at 700 (in Homo sapiens) 700 EQUAL O4'-phospho-L-tyrosine at 774 (in Homo sapiens) 774 EQUAL 1 EQUAL 906 EQUAL Reactome Database ID Release 82 9852753 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852753 Reactome R-MMU-912755 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912755.1 Reactome Database ID Release 82 9852755 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852755 Reactome R-MMU-912727 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912727.1 Cbl and Vav interact in thymocytes and peripheral T cells (Marengere et al. 1997). Cbl phosphorylated at Y700 binds Vav1 in 293T cells, leading to Vav ubiquitinylation and proteolytic degradation. 12881521 Pubmed 2003 Cbl-mediated ubiquitinylation and negative regulation of Vav Miura-Shimura, Y Duan, L Rao, NL Reddi, AL Shimura, H Rottapel, R Druker, BJ Tsygankov, A Band, V Band, H J Biol Chem 278:38495-504 9200440 Pubmed 1997 Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells Marengère, LE Mirtsos, C Kozieradzki, I Veillette, A Mak, TW Penninger, JM J Immunol 159:70-6 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 9927220 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9927220 Reactome R-MMU-912631 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912631.1 Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl negatively regulates PI3K via this mechanism (Dufour et al. 2008). The binding of Cbl to the p85 subunit of PI3K is mediated at least in part by tyrosine phosphorylation at Y731 (Dufour et al. 2008). Fyn and the related kinases Hck and Lyn are known to be associated with Cbl (Anderson et al. 1997, Hunter et al. 1999). Fyn is proven capable of Cbl Y731 phosphorylation (Hunter et al. 1999).The association of Fyn and Cbl has been described as constitutive (Hunter et al. 1999). CBL further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this also described as constitutive and mediated by the SH3 domain of p85. Binding of the SH2 domain of p85 to a specific phosphorylation site in Cbl is postulated to explain the the increase in Cbl/p85 association seen in activated cells (Panchamoorthy et al 1996) which negatively regulates PI3K activity (Fang et al. 2001). The negative effect of increased Cbl-PI3K interaction is mediated by Y731 of Cbl. Cbl binding increases PI3K ubiquitination and proteasome degradation (Dufour et al. 2008).<br><br><br>Cbl is constitutively associated with Grb in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain binds the adaptor protein CRKL. Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998). Cbl is tyrosine phosphorylated in response to many cytokines including IL-3, IL-2 (Gesbert et al. 1998) and IL-4 (Ueno et al. 1998). 9414268 Pubmed 1998 c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidylinositol 3'-kinase pathway Ueno, H Sasaki, K Honda, H Nakamoto, T Yamagata, T Miyagawa, K Mitani, K Yazaki, Y Hirai, H Blood 91:46-53 11526404 Pubmed 2001 Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells Fang, D Liu, YC Nat Immunol 2:870-5 9461587 Pubmed 1998 Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells Gesbert, F Garbay, C Bertoglio, J J Biol Chem 273:3986-93 inferred by electronic annotation IEA GO IEA IL3 stimulation induces Vav binding to Tec kinase IL3 stimulation induces Vav binding to Tec kinase This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 434625 1 1 EQUAL 845 EQUAL Reactome DB_ID: 9837248 1 UniProt:P24604 Tec Tec Tec FUNCTION Non-receptor tyrosine kinase that contributes to signaling from many receptors and participates as a signal transducer in multiple downstream pathways, including regulation of the actin cytoskeleton. Plays a redundant role to ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. Required for TCR-dependent IL2 gene induction. Phosphorylates DOK1, one CD28-specific substrate, and contributes to CD28-signaling. Mediates signals that negatively regulate IL2RA expression induced by TCR cross-linking. Plays a redundant role to BTK in BCR-signaling for B-cell development and activation, especially by phosphorylating STAP1, a BCR-signaling protein. Required in mast cells for efficient cytokine production. Involved in both growth and differentiation mechanisms of myeloid cells through activation by the granulocyte colony-stimulating factor CSF3, a critical cytokine to promoting the growth, differentiation, and functional activation of myeloid cells. Participates in platelet signaling downstream of integrin activation. Cooperates with JAK2 through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. GRB10, a negative modifier of the FOS activation pathway, is another substrate of TEC. TEC is involved in G protein-coupled receptor- and integrin-mediated signalings in blood platelets. Plays a role in hepatocyte proliferation and liver regeneration and is involved in HGF-induced ERK signaling pathway. TEC regulates also FGF2 unconventional secretion (endoplasmic reticulum (ER)/Golgi-independent mechanism) under various physiological conditions through phosphorylation of FGF2 'Tyr-82'. May also be involved in the regulation of osteoclast differentiation.ACTIVITY REGULATION Activated by tyrosine phosphorylation by a wide range of cytokine stimulations. When T-cells or B-cells receptors are activated, a series of phosphorylation leads to the recruitment of TEC to the cell membrane, where it is phosphorylated at Tyr-518. Also activated in response to SCF. Integrin engagement induces tyrosine phosphorylation of TEC in platelets. STAP1 participates in a positive feedback loop by increasing the activity of TEC. SOCS1 is an inhibitor of TEC kinase activity.SUBUNIT Interacts with INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with CD28, FASLG, FGF2, GRB10 and KIT (By similarity). Interacts with VAV1 and JAK2. Interacts with LYN.TISSUE SPECIFICITY Preferentially expressed in liver. Expression is also seen in the hematopoietic cells such as bone marrow, thymus and spleen. Lower expression is seen in the heart, kidney and ovary.DOMAIN The PH domain mediates the binding to inositol polyphosphate and phosphoinositides, leading to its targeting to the plasma membrane. It is extended in the BTK kinase family by a region designated the TH (Tec homology) domain, which consists of about 80 residues preceding the SH3 domain.DOMAIN The SH3 domain is essential for its targeting to activated CD28 costimulatory molecule.PTM Following B-cell or T-cell receptors engagement, translocates to the plasma membrane where it gets phosphorylated at Tyr-518. Undergoes also tyrosine phosphorylation during platelet activation.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. UniProt P24604 1 EQUAL 631 EQUAL Reactome DB_ID: 9852264 1 TEC:VAV1 [cytosol] TEC:VAV1 Reactome DB_ID: 434625 1 1 EQUAL 845 EQUAL Reactome DB_ID: 9837248 1 1 EQUAL 631 EQUAL Reactome Database ID Release 82 9852264 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852264 Reactome R-MMU-912729 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912729.1 Reactome Database ID Release 82 9852266 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852266 Reactome R-MMU-879914 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-879914.1 IL3 stimulation induces rapid and transient tyrosine-phosphorylation of Vav and the binding of Vav to Tec kinase through Tec homology domains. (Machide et al. 1995). Vav1 and Tec were seen to associate into a complex with the activated prolactin receptor (Kline et al. 2001). These reports were interpreted as Tec enhancing Vav GEF activity, but it has been suggested that Vav might contribute to Tec activation in T cell signaling (Reynolds et al. 2002). Tec kinases generally require PI3K-dependent membrane translocation and phosphorylation of the kinase domain, often by an Src family kinase, for activation (Takesono et al. 2002). 7651724 Pubmed 1995 Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain Machide, M Mano, H Todokoro, K Oncogene 11:619-25 11328862 Pubmed 2001 Activation and association of the Tec tyrosine kinase with the human prolactin receptor: mapping of a Tec/Vav1-receptor binding site Kline, JB Moore, DJ Clevenger, CV Mol Endocrinol 15:832-41 11994416 Pubmed 2002 Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways Reynolds, LF Smyth, LA Norton, T Freshney, N Downward, J Kioussis, D Tybulewicz, VL J Exp Med 195:1103-14 12118060 Pubmed 2002 Beyond calcium: new signaling pathways for Tec family kinases Takesono, A Finkelstein, LD Schwartzberg, PL J Cell Sci 115:3039-48 inferred by electronic annotation IEA GO IEA SHP1 and SHP2 bind the common beta chain SHP1 and SHP2 bind the common beta chain This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9844011 1 PTPN6,PTPN11 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PTPN6 [cytosol] PTPN11 [cytosol] UniProt P35235 Converted from EntitySet in Reactome Reactome DB_ID: 9852227 1 Reactome DB_ID: 9852663 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593,628)-Bc:SHP1, SHP2 [plasma membrane] High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593,628)-Bc:SHP1, SHP2 Converted from EntitySet in Reactome Reactome DB_ID: 9844011 1 Converted from EntitySet in Reactome Reactome DB_ID: 9852227 1 Reactome Database ID Release 82 9852663 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852663 Reactome R-MMU-914086 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-914086.1 Reactome Database ID Release 82 9852665 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852665 Reactome R-MMU-909738 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-909738.1 The common beta chain (Bc) has at least at least one direct binding site for SHP-1/SHP-2 (PTPN6/PTPN11). The SH2 domains of SHP1 and SHP2 associate with Y628 of Bc following IL-3 stimulation (Pei et al. 1994, Bone et al. 1997). SHPs act as regulators of signaling. SHP1 is thought to be a negative regulator of growth that terminates signals. Binding of SHP1 to EpoR leads to SHP1 activation and dephosphorylation of JAK2, terminating proliferative signals (Klingmuller et al. 1995). SHP1 has also been shown to interact directly and dephosphorylate JAK2 (Jiao et al. 1996). Although SHP-2 competes for the same binding site, it is thought to be a positive modulator. SHP2 associates with JAK1/2 and is phosphorylated at Y304 by these kinases, creating a GRB2 recognition motif (Yin et al. 1997). IL-3 induces the phosphorylation of SHP2 and its association with Grb2 (Welham et al. 1994). SHP2 could thereby act as an adaptor between Bc and Grb2 leading to activation of the ras/mitogen-activated protein kinase pathway. SHP2 can also associate with the p85 subunit of phosphatidylinositol 3-kinase (Welham et al. 1994) so SHP2 may also regulate this pathway. 9162089 Pubmed 1997 SHP1 and SHP2 protein-tyrosine phosphatases associate with betac after interleukin-3-induced receptor tyrosine phosphorylation. Identification of potential binding sites and substrates Bone, H Dechert, U Jirik, F Schrader, JW Welham, MJ J Biol Chem 272:14470-6 8943354 Pubmed 1996 Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1 Jiao, H Berrada, K Yang, W Tabrizi, M Platanias, LC Yi, T Mol Cell Biol 16:6985-92 7889566 Pubmed 1995 Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals Klingmüller, U Lorenz, U Cantley, Lewis C Neel, BG Lodish, HF Cell 80:729-38 7528537 Pubmed 1994 Intramolecular regulation of protein tyrosine phosphatase SH-PTP1: a new function for Src homology 2 domains Pei, D Lorenz, U Klingmüller, U Neel, BG Walsh, CT Biochemistry 33:15483-93 8995399 Pubmed 1997 Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases Yin, T Shen, R Feng, GS Yang, YC J Biol Chem 272:1032-7 7522233 Pubmed 1994 Interleukin (IL)-3 and granulocyte/macrophage colony-stimulating factor, but not IL-4, induce tyrosine phosphorylation, activation, and association of SHPTP2 with Grb2 and phosphatidylinositol 3'-kinase Welham, MJ Dechert, U Leslie, KB Jirik, F Schrader, JW J Biol Chem 269:23764-8 inferred by electronic annotation IEA GO IEA 3.1.3.48 SHP1 and SHP2 dephosphorylate Y628 of IL3RB SHP1 and SHP2 dephosphorylate Y628 of IL3RB This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9852663 1 Reactome DB_ID: 9853460 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593)-Bc:SHP1, SHP2 [plasma membrane] High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593)-Bc:SHP1, SHP2 Converted from EntitySet in Reactome Reactome DB_ID: 9844011 1 Converted from EntitySet in Reactome Reactome DB_ID: 9853458 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593)-Bc [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 82 9853460 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853460 Reactome R-MMU-914049 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-914049.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9852663 GO 0004725 GO molecular function Reactome Database ID Release 82 9853461 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853461 Reactome Database ID Release 82 9853463 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853463 Reactome R-MMU-914036 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-914036.1 Synthetic phosphopeptides based on Bc were dephosphorylated by SHP1 and SHP2, peptides phosphorylated at Y628 were the best substrate followed by those phosphorylated at Y766. inferred by electronic annotation IEA GO IEA 2.7.11.11 IL3RB is phosphorylated on Ser-585 IL3RB is phosphorylated on Ser-585 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9852225 1 Converted from EntitySet in Reactome Reactome DB_ID: 9852776 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 163497 UniProt:P05132 Prkaca Prkaca Prkaca Pkaca FUNCTION Phosphorylates a large number of substrates in the cytoplasm and the nucleus (By similarity). Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP (PubMed:10805756, PubMed:19223768). Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (By similarity). RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts (By similarity). Involved in chondrogenesis by mediating phosphorylation of SOX9 (PubMed:10805756). Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis (By similarity). Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation (PubMed:19223768). May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity). Phosphorylates APOBEC3G and AICDA. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (By similarity).ACTIVITY REGULATION Allosterically activated by various compounds, including ATP. Activated by cAMP; the nucleotide acts as a dynamic and allosteric activator by coupling the two lobes of apo PKA, enhancing the enzyme dynamics synchronously and priming it for catalysis.SUBUNIT A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. Protein kinase A holoenzyme is comprised of two catalytic (C) and two regulatory (R) subunits which keep the enzyme in an inhibited state before activation by cyclic-AMP. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. The cAMP-dependent protein kinase catalytic subunit binds PJA2. Both isoforms 1 and 2 forms activate cAMP-sensitive PKAI and PKAII holoenzymes by interacting with regulatory subunit (R) of PKA, PRKAR1A/PKR1 and PRKAR2A/PKR2, respectively. Interacts with PRKAR1A and PRKAR2B (By similarity). Interacts with NFKB1, NFKB2 and NFKBIA in platelets; these interactions are disrupted by thrombin and collagen. Binds to ABL1 in spermatozoa and with CDC25B in oocytes. Interacts with APOBEC3G and AICDA (By similarity). Interacts with RAB13; downstream effector of RAB13 involved in tight junction assembly (By similarity). Found in a complex at least composed of MROH2B isoform 2, PRKACA isoform 2 and TCP11 (PubMed:27105888). Interacts with MROH2B isoform 2 (PubMed:27105888). Interacts with HSF1 (By similarity). Isoform 2 interacts with TCP11 (PubMed:27105888).TISSUE SPECIFICITY Isoform 2 is sperm specific.DEVELOPMENTAL STAGE Accumulates in oocytes before fertilization but fades out after fertilization.PTM Autophosphorylated. Phosphorylation is enhanced by vitamin K(2) (By similarity). Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity.PTM Asn-3 is partially deaminated to Asp-3 giving rise to 2 major isoelectric variants, called CB and CA respectively.PTM When myristoylated, Ser-11 is autophosphorylated probably in conjunction with deamidation of Asn-3.PTM Phosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficiency.DISRUPTION PHENOTYPE Frequent early postnatal lethality. Survivals are runted accompanied with mature sperm exhibiting defective forward motility.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily. UniProt P05132 2 EQUAL 351 EQUAL GO 0004691 GO molecular function Reactome Database ID Release 82 164051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164051 Reactome Database ID Release 82 9852800 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852800 Reactome R-MMU-913451 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-913451.1 GM-CSF and IL-3 application lead to Ser-585 phosphorylation of the Common beta chain (Bc) shared with the IL-3 and IL-5 receptors (Stomski et al. 1999, Guthridge et al. 2000). PKA was identified as capable of phosphorylating Bc at S585 (Guthridge et al. 2000). 10477722 Pubmed 1999 Identification of a 14-3-3 binding sequence in the common beta chain of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors that is serine-phosphorylated by GM-CSF Stomski, FC Dottore, M Winnall, W Guthridge, MA Woodcock, J Bagley, CJ Thomas, DT Andrews, RK Berndt, MC Lopez, Angel Blood 94:1933-42 10949031 Pubmed 2000 Site-specific serine phosphorylation of the IL-3 receptor is required for hemopoietic cell survival Guthridge, MA Stomski, FC Barry, EF Winnall, W Woodcock, JM McClure, BJ Dottore, M Berndt, MC Lopez, Angel Mol Cell 6:99-108 inferred by electronic annotation IEA GO IEA p-S585-IL3RB binds 14-3-3 proteins p-S585-IL3RB binds 14-3-3 proteins This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9820761 1 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 Converted from EntitySet in Reactome Reactome DB_ID: 9852776 1 Reactome DB_ID: 9852778 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta [plasma membrane] High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta Reactome DB_ID: 9820761 1 1 EQUAL 245 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9852776 1 Reactome Database ID Release 82 9852778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852778 Reactome R-MMU-914180 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-914180.1 Reactome Database ID Release 82 9852780 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9852780 Reactome R-MMU-912757 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-912757.1 The common beta chain (Bc), binds 14-3-3 zeta at a site that requires phosphorylation of Serine 585 (Stomski et al. 1999). Bc modifications that prevent Ser-585 phosphorylation do not recruit 14-3-3 zeta (Guthridge et al. 2000). inferred by electronic annotation IEA GO IEA 14-3-3 zeta binding allows recruitment of PI3K 14-3-3 zeta binding allows recruitment of PI3K This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9852778 1 Converted from EntitySet in Reactome Reactome DB_ID: 9851207 1 Reactome DB_ID: 9853465 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta:p85-containing Class 1A PI3Ks [plasma membrane] High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta:p85-containing Class 1A PI3Ks Reactome DB_ID: 9852778 1 Converted from EntitySet in Reactome Reactome DB_ID: 9851207 1 Reactome Database ID Release 82 9853465 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853465 Reactome R-MMU-914177 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-914177.1 Reactome Database ID Release 82 9853467 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9853467 Reactome R-MMU-914182 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-914182.1 Immunoprecipitation and kinase activity experiments demonstrated that Ser-585 phosphorylation of the common beta chain (Bc) was required for activation of PI3K activity in response to IL-3 and co-precipitation of Bc, 14-3-3 zeta and the p85 subunit of Class 1A PI3 kinases (Guthridge et al. 2000). Subsequent experiments confirmed that Ser-585 phosphorylation and PI3K activation are required to promote cell survival in response to GM-CSF, but not for proliferation responses, and that this mechanism is independent of Bc tyrosine phosphorylation (Guthridge et al. 2004). This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors; the other involves Bc tyrosine-593 phosphorylation-mediated recruitment of SHC1, GRB2 and GAB2. 12920017 Pubmed 2004 The phosphoserine-585-dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hematopoietic cell survival through activation of NF-kappaB and induction of bcl-2 Guthridge, MA Barry, EF Felquer, FA McClure, BJ Stomski, FC Ramshaw, H Lopez, Angel Blood 103:820-7 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 9927156 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9927156 Reactome R-MMU-512988 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-512988.1 GO 0019221 GO biological process The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains.<br><br> IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009).<br><br> All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008).<br><br> The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).<br><br><br><br>Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed. 1590989 Pubmed 1992 Cytokine receptors and signal transduction Miyajima, A Kitamura, T Harada, N Yokota, T Arai, K Annu Rev Immunol 10:295-331 10450743 Pubmed 1999 Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs Blalock, WL Weinstein-Oppenheimer, C Chang, F Hoyle, PE Wang, XY Algate, PA Franklin, RA Oberhaus, SM Steelman, LS McCubrey, JA Leukemia 13:1109-66 19819937 Pubmed 2009 IL-5- and eosinophil-mediated inflammation: from discovery to therapy Kouro, T Takatsu, K Int Immunol 21:1303-9 9794243 Pubmed 1998 Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family de Groot, RP Coffer, PJ Koenderman, L Cell Signal 10:619-28 19436055 Pubmed 2009 The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease Hercus, TR Thomas, D Guthridge, MA Ekert, PG King-Scott, J Parker, MW Lopez, Angel Blood 114:1289-98 11312115 Pubmed 2001 Specificity in cytokine signal transduction: lessons learned from the IL-3/IL-5/GM-CSF receptor family Geijsen, N Koenderman, L Coffer, PJ Cytokine Growth Factor Rev 12:19-25 7896837 Pubmed 1995 A membrane proximal domain of the human interleukin-3 receptor beta c subunit that signals DNA synthesis in NIH 3T3 cells specifically binds a complex of Src and Janus family tyrosine kinases and phosphatidylinositol 3-kinase Rao, P Mufson, RA J Biol Chem 270:6886-93 inferred by electronic annotation IEA GO IEA