BioPAX pathway converted from "RET signaling" in the Reactome database.RET signalingRET signalingThe RET proto-oncogene encodes a receptor tyrosine kinase expressed primarily in urogenital precursor cells, spermatogonocytes, dopaminergic neurons, motor neurons and neural crest progenitors and derived cells. . It is essential for kidney genesis, spermatogonial self-renewal and survivial, specification, migration, axonal growth and axon guidance of developing enteric neurons, motor neurons, parasympathetic neurons and somatosensory neurons (Schuchardt et al. 1994, Enomoto et al. 2001, Naughton et al. 2006, Kramer et al. 2006, Luo et al. 2006, 2009). RET was identified as the causative gene for human papillary thyroid carcinoma (Grieco et al. 1990), multiple endocrine neoplasia (MEN) type 2A (Mulligan et al. 1993), type 2B (Hofstra et al. 1994, Carlson et al. 1994), and Hirschsprung's disease (Romeo et al. 1994, Edery et al. 1994). <br><br>RET contains a cadherin-related motif and a cysteine-rich domain in the extracellular domain (Takahashi et al. 1988). It is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands, GDNF (Lin et al. 1993), neurturin (NRTN) (Kotzbauer et al. 1996), artemin (ARTN) (Baloh et al. 1998), and persephin (PSPN) (Milbrandt et al. 1998), which form a family of neurotrophic factors. To stimulate RET, these ligands need a glycosylphosphatidylinositol (GPI)-anchored co-receptor, collectively termed GDNF family receptor-alpha (GFRA) (Treanor et al. 1996, Jing et al. 1996). The four members of this family have different, overlapping ligand preferences. GFRA1, GFRA2, GFRA3, and GFRA4 preferentially bind GDNF, NRTN, ARTN and PSPN, respectively (Jing et al. 1996, 1997, Creedon et al. 1997, Baloh et al. 1997, 1998, Masure et al. 2000). The GFRA co-receptor can come from the same cell as RET, or from a different cell. When the co-receptor is produced by the same cell as RET, it is termed cis signaling. When the co-receptor is produced by another cell, it is termed trans signaling. Cis and trans activation has been proposed to diversify RET signaling, either by recruiting different downstream effectors or by changing the kinetics or efficacy of kinase activation (Tansey et al. 2000, Paratcha et al. 2001). Whether cis and trans signaling has significant differences in vivo is unresolved (Fleming et al. 2015). Different GDNF family members could activate similar downstream signaling pathways since all GFRAs bind to and activate the same tyrosine kinase and induce coordinated phosphorylation of the same four RET tyrosines (Tyr905, Tyr1015, Tyr1062, and Tyr1096) with similar kinetics (Coulpier et al. 2002). However the exact RET signaling pathways in different types of cells and neurons remain to be determined.Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28RET binds GFRA1,GFRA3RET binds GFRA1,GFRA3RET is a receptor tyrosine kinase with a cadherin-related motif and a cysteine-rich domain in the extracellular domain (Takahashi et al. 1988). It is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands (Lin et al. 1993, Kotzbauer et al. 1996, Baloh et al. 1998, Milbrandt et al. 1998). RET can only bind these ligands in the presence of a co-receptor from the family of glycosylphosphatidylinositol (GPI)-anchored co-receptors collectively termed GDNF family receptor-alpha (GFRA) (Treanor et al. 1996, Jing et al. 1996, Plaza-Menacho et al. 2006). Early models proposed that GDNF formed a complex with GFRA1 and subsequently recruited RET (Massagué et al. 1996). Current models suggest that GFRA and RET pre-associate before ligand binding, based on binding and site-directed mutagenesis studies (Eketjäll et al. 1999, Cik et al. 2000). An alternative model suggests that GPI-anchored GFRA recruits RET to lipid rafts after GDNF stimulation (Tansey et al. 2000). The stoichiometry as well as the kinetics of ligand-receptor complex formation are not well understood. It is believed that all GDNF family members interact with their cognate co-receptor and activate RET in a similar manner to GDNF (Airaksinen & Saarma 2002). Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88537971plasma membraneGO0005886UniProt:P07949 RETRETRETCDHF12CDHR16RET51PTCFUNCTION Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which induces inhibition of food-intake. Activates MAPK- and AKT-signaling pathways (PubMed:28846097, PubMed:28953886, PubMed:28846099). Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL (PubMed:28846099).ACTIVITY REGULATION Repressed by 4-(3-hydroxyanilino)-quinolines derivatives, indolin-2-one-derivatives, 2-(alkylsulfanyl)-4-(3-thienyl) nicotinonitrile analogs, 3- and 4-substituted beta-carbolin-1-ones, vandetanib, motesanib, sorafenib (BAY 43-9006), cabozantinib (XL184), sunitinib, and withaferin A (WA). Inactivation by sorafenib both reduces kinase activity and promotes lysosomal degradation.SUBUNIT Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5 (By similarity). The phosphorylated form interacts with PLCG1 and GRB7 (By similarity). Interacts (not phosphorylated) with PTK2/FAK1 (via FERM domain) (PubMed:21454698). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas (PubMed:21357690). Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex (PubMed:19366855). Binds to ARTN (By similarity). Interacts (inactive) with CBLC and CD2AP; dissociates upon activation by GDNF which increases CBLC:CD2AP interaction (PubMed:18753381). Interacts (via the extracellular domain) with GFRAL (via the extracellular domain); the interaction mediates cellular signaling upon interaction of GFRAL with its ligand GDF15 (PubMed:28953886, PubMed:28846097, PubMed:28846099). Interaction with GFRAL requires previous GDF15-binding to GFRAL (PubMed:28846097, PubMed:28846099). Interacts with GFRA1; in the presence of SORL1, the GFRA1/RET complex is targeted to endosomes (PubMed:23333276). Interacts with GDNF (PubMed:21994944).INDUCTION Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3.PTM Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr-1062.PTM Proteolytically cleaved by caspase-3. The soluble RET kinase fragment is able to induce cell death. The extracellular cell-membrane anchored RET cadherin fragment accelerates cell adhesion in sympathetic neurons.POLYMORPHISM The Cys-982 polymorphism may be associated with an increased risk for developing Hirschsprung disease.DISEASE Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs) (PubMed:12787916, PubMed:2406025, PubMed:10980597, PubMed:10439047). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene (PubMed:2406025). Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene. Translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene (PubMed:2734021). Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion (PubMed:10980597). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene (PubMed:12787916). Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene (PubMed:10439047). Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene (PubMed:10439047). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene (PubMed:3037315).DISEASE Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis.MISCELLANEOUS Treatment with withaferin A (WA) leads tumor regression in medullary thyroid carcinomas (MTC).SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtP07949Chain Coordinates29EQUAL1114EQUALConverted from EntitySet in ReactomeReactome DB_ID: 88537991GFRA1,GFRA3 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGFRA3 [plasma membrane]GFRA1 [plasma membrane]UniProtO60609UniProtP56159Reactome DB_ID: 88557451RET:GFRA1,GFRA3 [plasma membrane]RET:GFRA1,GFRA3Reactome DB_ID: 8853797129EQUAL1114EQUALConverted from EntitySet in ReactomeReactome DB_ID: 88537991Reactome Database ID Release 758855745Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855745ReactomeR-HSA-88557452Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855745.2Reactome Database ID Release 758853745Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853745ReactomeR-HSA-88537453Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853745.316979782Pubmed2006Current concepts in RET-related genetics, signaling and therapeuticsPlaza-Menacho, IvanBurzynski, Grzegorz Mde Groot, Jan WillemEggen, Bart J LHofstra, Robert M WTrends Genet. 22:627-3611988777Pubmed2002The GDNF family: signalling, biological functions and therapeutic valueAiraksinen, Matti SSaarma, MartNat. Rev. Neurosci. 3:383-949192684Pubmed1997Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neuronsCreedon, D JTansey, M GBaloh, R HOsborne, P ALampe, P AFahrner, T JHeuckeroth, R OMilbrandt, JJohnson, E MProc. Natl. Acad. Sci. U.S.A. 94:7018-238674117Pubmed1996GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNFJing, SWen, DYu, YHolst, P LLuo, YFang, MTamir, RAntonio, LHu, ZCupples, RLouis, J CHu, SAltrock, B WFox, G MCell 85:1113-243078962Pubmed1988Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domainsTakahashi, MBuma, YIwamoto, TInaguma, YIkeda, HHiai, HOncogene 3:571-89883723Pubmed1998Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complexBaloh, R HTansey, M GLampe, P AFahrner, T JEnomoto, HSimburger, K SLeitner, M LAraki, TJohnson, E MMilbrandt, JNeuron 21:1291-3028493557Pubmed1993GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neuronsLin, L FDoherty, D HLile, J DBektesh, SCollins, FScience 260:1130-29491986Pubmed1998Persephin, a novel neurotrophic factor related to GDNF and neurturinMilbrandt, Jde Sauvage, FJFahrner, T JBaloh, R HLeitner, M LTansey, M GLampe, P AHeuckeroth, R OKotzbauer, P TSimburger, K SGolden, J PDavies, J AVejsada, RKato, A CHynes, MSherman, DNishimura, MWang, L CVandlen, RMoffat, BKlein, R DPoulsen, KGray, CGarces, AJohnson, E MNeuron 20:245-5310545102Pubmed1999Distinct structural elements in GDNF mediate binding to GFRalpha1 and activation of the GFRalpha1-c-Ret receptor complexEketjäll, SFainzilber, MMurray-Rust, JIbáñez, C FEMBO J. 18:5901-1010829012Pubmed2000Binding of GDNF and neurturin to human GDNF family receptor alpha 1 and 2. Influence of cRET and cooperative interactionsCik, MMasure, SLesage, A SVan der Linden, IVan Gompel, PPangalos, M NGordon, R DLeysen, J EJ. Biol. Chem. 275:27505-128945474Pubmed1996Neurturin, a relative of glial-cell-line-derived neurotrophic factorKotzbauer, P TLampe, P AHeuckeroth, R OGolden, J PCreedon, D JJohnson, E MMilbrandt, JNature 384:467-708657309Pubmed1996Characterization of a multicomponent receptor for GDNFTreanor, J JGoodman, Lde Sauvage, FStone, D MPoulsen, K TBeck, C DGray, CArmanini, M PPollock, R AHefti, FPhillips, H SGoddard, AMoore, M WBuj-Bello, ADavies, A MAsai, NTakahashi, MVandlen, RHenderson, C ERosenthal, ANature 382:80-38657299Pubmed1996Neurotrophic factors. Crossing receptor boundariesMassagué, JNature 382:29-3010774729Pubmed2000GFRalpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survivalTansey, M GBaloh, R HMilbrandt, JJohnson, E MNeuron 25:611-23RET binds GFRA1,GFRA2RET binds GFRA1,GFRA2RET is a receptor tyrosine kinase with a cadherin-related motif and a cysteine-rich domain in the extracellular domain (Takahashi et al. 1988). It is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands (Lin et al. 1993, Kotzbauer et al. 1996, Baloh et al. 1998, Milbrandt et al. 1998). RET can only bind these ligands in the presence of a co-receptor from the family of glycosylphosphatidylinositol (GPI)-anchored co-receptors collectively termed GDNF family receptor-alpha (GFRA) (Treanor et al. 1996, Jing et al. 1996, Plaza-Menacho et al. 2006). Earlier models proposed that GDNF formed a complex with GFRA1 and subsequently recruited RET (Massagué et al. 1996). Current models suggest that GFRA and RET preassociate before ligand binding, based on binding and site-directed mutagenesis studies (Eketjäll et al. 1999, Cik et al. 2000). An alternative model suggests that GPI-anchored GFRA recruits RET to lipid rafts after GDNF stimulation (Tansey et al. 2000). The stoichiometry as well as the kinetics of ligand-receptor complex formation are not well understood. It is believed that all GDNF family members interact with their cognate co-receptor and activate RET in a similar manner to GDNF (Airaksinen & Saarma 2002). Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 8853797129EQUAL1114EQUALConverted from EntitySet in ReactomeReactome DB_ID: 88538031GFRA1, GFRA2 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGFRA2 [plasma membrane]GFRA1 [plasma membrane]UniProtO00451Reactome DB_ID: 88557591RET:GFRA1,GFRA2 [plasma membrane]RET:GFRA1,GFRA2Reactome DB_ID: 8853797129EQUAL1114EQUALConverted from EntitySet in ReactomeReactome DB_ID: 88538031Reactome Database ID Release 758855759Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855759ReactomeR-HSA-88557592Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855759.2Reactome Database ID Release 758871226Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8871226ReactomeR-HSA-88712263Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8871226.3RET binds GFRA4RET binds GFRA4RET is a receptor tyrosine kinase with a cadherin-related motif and a cysteine-rich domain in the extracellular domain (Takahashi et al. 1988). It is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands (Lin et al. 1993, Kotzbauer et al. 1996, Baloh et al. 1998, Milbrandt et al. 1998). RET can only bind these ligands in the presence of a co-receptor from the family of glycosylphosphatidylinositol (GPI)-anchored co-receptors collectively termed GDNF family receptor-alpha (GFRA) (Treanor et al. 1996, Jing et al. 1996, Plaza-Menacho et al. 2006). Early models proposed that GDNF formed a complex with GFRA1 and subsequently recruited RET (Massagué et al. 1996). Current models suggest that GFRA and RET preassociate before ligand binding, based on binding and site-directed mutagenesis studies (Eketjäll et al. 1999, Cik et al. 2000). An alternative model suggests that GPI-anchored GFRA recruits RET to lipid rafts after GDNF stimulation (Tansey et al. 2000). The stoichiometry as well as the kinetics of ligand-receptor complex formation are not well understood. It is believed that all GDNF family members interact with their cognate co-receptor and activate RET in a similar manner to GDNF (Airaksinen & Saarma 2002). Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 8853797129EQUAL1114EQUALReactome DB_ID: 4349001UniProt:Q9GZZ7 GFRA4GFRA4GFRA4FUNCTION Receptor for persephin. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor. May be important in C-cell development and, in the postnatal development of the adrenal medulla.SUBUNIT Interacts with SORL1.TISSUE SPECIFICITY Predominantly expressed in the adult thyroid gland. Low levels also found in fetal adrenal and thyroid glands.SIMILARITY Belongs to the GDNFR family.UniProtQ9GZZ721EQUAL278EQUALReactome DB_ID: 88557511RET:GFRA4 [plasma membrane]RET:GFRA4Reactome DB_ID: 8853797129EQUAL1114EQUALReactome DB_ID: 434900121EQUAL278EQUALReactome Database ID Release 758855751Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855751ReactomeR-HSA-88557512Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855751.2Reactome Database ID Release 758871227Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8871227ReactomeR-HSA-88712273Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8871227.3GDNF,NRTN bind RET:GFRA1,GFRA2GDNF,NRTN bind RET:GFRA1,GFRA2Glial cell-derived neurotrophic factor (GDNF) (Lin et al. 1993) and neurturin (NRTN) (Kotzbauer et al. 1996) are ligands for GDNF family receptor-alpha (GFRA) 1 and 2 (Jing et al. 1996, 1997, Creedon et al. 1997, Baloh et al. 1997). Despite the cross activation in vitro, GDNF preferentially acts through RET:GFRA1 (Schuchardt et al. 1994, Moore et al. 1996, Pichel et al. 1996, Sanchez et al. 1996, Calcano et al. 1998, Endomoto et al. 1998, whereas NRTN preferentially acts through RET: GFRA2 (Heuckeroth et al. 1999, Rossi et al. 1999, Luo et al. 2004, 2009, Lindfors et al. 2006) in vivo. Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Converted from EntitySet in ReactomeReactome DB_ID: 88538021extracellular regionGO0005576GDNF,NRTN [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGDNF [extracellular region]NRTN [extracellular region]UniProtP39905UniProtQ99748Reactome DB_ID: 88557591Reactome DB_ID: 88538051RET:GFRA1,GFRA2:GDNF,NRTN [plasma membrane]RET:GFRA1,GFRA2:GDNF,NRTNConverted from EntitySet in ReactomeReactome DB_ID: 88538021Reactome DB_ID: 88557591Reactome Database ID Release 758853805Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853805ReactomeR-HSA-88538052Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853805.2Reactome Database ID Release 758853789Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853789ReactomeR-HSA-88537893Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853789.39407096Pubmed1997GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF familyJing, SYu, YFang, MHu, ZHolst, P LBoone, TDelaney, JSchultz, HZhou, RFox, G MJ. Biol. Chem. 272:33111-717553423Pubmed2007A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neuronsLuo, WenqinWickramasinghe, S RasikaSavitt, Joseph MGriffin, John WDawson, Ted MGinty, David DNeuron 54:739-5416481427Pubmed2006Deficient nonpeptidergic epidermis innervation and reduced inflammatory pain in glial cell line-derived neurotrophic factor family receptor alpha2 knock-out miceLindfors, Päivi HVõikar, VooteleRossi, JariAiraksinen, Matti SJ. Neurosci. 26:1953-609697851Pubmed1998GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidneyCacalano, GFariñas, IWang, L CHagler, KForgie, AMoore, MArmanini, MPhillips, HRyan, A MReichardt, L FHynes, MDavies, ARosenthal, ANeuron 21:53-628657308Pubmed1996Renal and neuronal abnormalities in mice lacking GDNFMoore, M WKlein, R DFariñas, ISauer, HArmanini, MPhillips, HReichardt, L FRyan, A MCarver-Moore, KRosenthal, ANature 382:76-99182803Pubmed1997TrnR2, a novel receptor that mediates neurturin and GDNF signaling through RetBaloh, R HTansey, M GGolden, J PCreedon, D JHeuckeroth, R OKeck, C LZimonjic, D BPopescu, N CJohnson, E MMilbrandt, JNeuron 18:793-8028657307Pubmed1996Defects in enteric innervation and kidney development in mice lacking GDNFPichel, J GShen, LSheng, H ZGranholm, A CDrago, JGrinberg, ALee, E JHuang, S PSaarma, MHoffer, B JSariola, HWestphal, HNature 382:73-620064391Pubmed2009Molecular identification of rapidly adapting mechanoreceptors and their developmental dependence on ret signalingLuo, WenqinEnomoto, HidekiRice, Frank LMilbrandt, JeffreyGinty, David DNeuron 64:841-5610069332Pubmed1999Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neuronsHeuckeroth, R OEnomoto, HGrider, J RGolden, J PHanke, J AJackman, AMolliver, D CBardgett, M ESnider, W DJohnson, E MMilbrandt, JNeuron 22:253-638657306Pubmed1996Renal agenesis and the absence of enteric neurons in mice lacking GDNFSánchez, M PSilos-Santiago, IFrisén, JHe, BLira, S ABarbacid, MNature 382:70-39728913Pubmed1998GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneysEnomoto, HAraki, TJackman, AHeuckeroth, R OSnider, W DJohnson, E MMilbrandt, JNeuron 21:317-2410069331Pubmed1999Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFR alpha2, a functional neurturin receptorRossi, JLuukko, KPoteryaev, DLaurikainen, ASun, Y FLaakso, TEerikäinen, STuominen, RLakso, MRauvala, HArumäe, UPasternack, MSaarma, MAiraksinen, M SNeuron 22:243-52ARTN binds RET:GFRA1,GFRA3ARTN binds RET:GFRA1,GFRA3Artemin (ARTN) is a ligand for GDNF family receptor-alpha (GFRA) 1 and 3, preferentially binding GFRA3 (Baloh et al. 1998).Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 4349031UniProt:Q5T4W7 ARTNARTNARTNEVNFUNCTION Ligand for the GFR-alpha-3-RET receptor complex but can also activate the GFR-alpha-1-RET receptor complex. Supports the survival of sensory and sympathetic peripheral neurons in culture and also supports the survival of dopaminergic neurons of the ventral mid-brain. Strong attractant of gut hematopoietic cells thus promoting the formation Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue.SUBUNIT Homodimer; disulfide-linked. Binds to RET (By similarity).TISSUE SPECIFICITY Ubiquitous. Expressed at high levels in peripheral tissues including prostate, placenta, pancreas, heart, kidney, pituitary gland, lung and testis. Expressed at low levels in the brain.DEVELOPMENTAL STAGE Expressed during embryogenesis. High level expression seen in fetal kidney and lung while a low level expression seen in the fetal brain.SIMILARITY Belongs to the TGF-beta family. GDNF subfamily.UniProtQ5T4W7108EQUAL220EQUALReactome DB_ID: 88557451Reactome DB_ID: 88537951RET:GFRA1,GFRA3:ARTN [plasma membrane]RET:GFRA1,GFRA3:ARTNReactome DB_ID: 4349031108EQUAL220EQUALReactome DB_ID: 88557451Reactome Database ID Release 758853795Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853795ReactomeR-HSA-88537952Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853795.2Reactome Database ID Release 758853800Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853800ReactomeR-HSA-88538002Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853800.2PSPN binds RET:GFRA4PSPN binds RET:GFRA4Persephin (PSPN) is a ligand for GDNF family receptor-alpha (GFRA) 4 (Milbrandt et al. 1998, Masure et al. 2000).Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 4349071UniProt:O60542 PSPNPSPNPSPNFUNCTION Exhibits neurotrophic activity on mesencephalic dopaminergic and motor neurons.SUBUNIT Homodimer; disulfide-linked.SIMILARITY Belongs to the TGF-beta family. GDNF subfamily.UniProtO6054222EQUAL156EQUALReactome DB_ID: 88557511Reactome DB_ID: 88537981RET:GFRA4:PSPN [plasma membrane]RET:GFRA4:PSPNReactome DB_ID: 434907122EQUAL156EQUALReactome DB_ID: 88557511Reactome Database ID Release 758853798Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853798ReactomeR-HSA-88537982Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853798.2Reactome Database ID Release 758853801Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853801ReactomeR-HSA-88538013Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853801.310958791Pubmed2000Mammalian GFRalpha -4, a divergent member of the GFRalpha family of coreceptors for glial cell line-derived neurotrophic factor family ligands, is a receptor for the neurotrophic factor persephinMasure, SCik, MHoefnagel, ENosrat, C AVan der Linden, IScott, RVan Gompel, PLesage, A SVerhasselt, PIbáñez, C FGordon, R DJ. Biol. Chem. 275:39427-34RET dimerizesRET dimerizesIt is widely accepted that RET undergoes dimerization and transphosphorylation following Glial cell line-derived neurotrophic factor (GDNF) binding to the GDNF-family receptor:RET complex. Transphosphorylation of specific tyrosine residues is a prerequisite for activation of RET tyrosine kinase activity and downstream signaling (Santoro et al. 1995, Airaksinen et al. 1999, Takeda et al. 2001, Leppänen et al. 2004). However, self-association of RET in the absence of GDNF has been reported and may contribute to the mechanism of RET activation (Kjaer et al. 2006). The stoichiometry and kinetics of ligand-receptor complex formation are not well understood. It is assumed that all GDNF family of ligands (GFL) members interact with their cognate co-receptor and activate RET in a similar manner to GDNF (Airaksinen & Saarma 2002). Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Converted from EntitySet in ReactomeReactome DB_ID: 88538172RET:GFRA:GDNF complexes [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 885381812x RET:GFRA:GDNF complexes [plasma membrane]2x RET:GFRA:GDNF complexesConverted from EntitySet in ReactomeReactome DB_ID: 88538172Reactome Database ID Release 758853818Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853818ReactomeR-HSA-88538182Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853818.2Reactome Database ID Release 758853762Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853762ReactomeR-HSA-88537622Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853762.211491658Pubmed2001Osmotic stress-mediated activation of RET kinases involves intracellular disulfide-bonded dimer formationTakeda, KKato, MWu, JIwashita, TSuzuki, HTakahashi, MNakashima, IAntioxid. Redox Signal. 3:473-8215044950Pubmed2004The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activationLeppänen, Veli-MattiBespalov, Maxim MRuneberg-Roos, PiaPuurand, UloMerits, AndresSaarma, MartGoldman, AdrianEMBO J. 23:1452-6216732321Pubmed2006Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutationsKjaer, SKurokawa, KPerrinjaquet, MAbrescia, CIbáñez, C FOncogene 25:7086-9510356294Pubmed1999GDNF family neurotrophic factor signaling: four masters, one servant?Airaksinen, M STitievsky, ASaarma, MMol. Cell. Neurosci. 13:313-257824936Pubmed1995Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2BSantoro, MCarlomagno, FRomano, ABottaro, D PDathan, N AGrieco, MFusco, AVecchio, GMatoskova, BKraus, M HScience 267:381-32.7.10.1RET tyrosine phosphorylationRET tyrosine phosphorylationRET undergoes trans-autophosphorylation on specific tyrosine (Y) residues. The short and medium-length isoforms of RET contain 16 tyrosine residues; 10 in the kinase domain, 2 in the juxtamembrane domain, 1 in the kinase insert and 3 in the carboxy-terminal tail. The long RET isoform has 2 additional tyrosines in the carboxy-terminal tail. Phosphorylation of Y905 stabilizes the active conformation of the kinase and facilitates the autophosphorylation of Y residues mainly located in the C-terminal tail (Iwashita et al. 1996, Kawamoto et 2004). Y905, 1015, 1062 and 1096 are binding sites for GRB7/GRB10, phospholipase Cgamma (PLCG1), SHC1 and GRB2, respectively (Ichihara et al. 2004, Murakumo et al. 2006). Y1096 is present only in the long isoform. Phosphorylated Y981 is reported to bind SRC (Encinas et al. 2004). <br><br>RET can activate various signaling pathways including RAS-RAF-ERK (van Weering et al. 1995, Ohiwa et al. 1997, van Weering & Bos 1997, Trupp et al. 1999, Hayashi et al. 2000), phosphatidylinositol 3-kinase (PI3K)/AKT (Murakami et al. 1999a, Murakami et al. 1999b, Trupp et al. 1999, Soler et al. 1999, Segouffin-Cariou & Billaud 2000, Hayashi et al. 2000), p38 mitogen-activated protein kinase (MAPK) (Worby et al. 1996, Feng et al. 1999) and c-Jun N-terminal kinase (JNK) pathways (Xing et al. 1998, Chiariello et al. 1998). All these pathways are activated mainly through Y1062 (Hayashi et al. 2000). Point mutations at Y1062 result in a severe loss-of-function phenotype (Ibáñez 2013). SHC1 further associates with GRB2 and GAB1/GAB2, all of which become tyrosine phosphorylated. Tyrosine-phosphorylated GAB1/2 associates with the p85 subunit of PI3K, resulting in PI3K and AKT activation (Murakami et al. 1999b, Hayashi et al. 2000, Besset et al. 2000). GRB2-GAB1/2 can also assemble directly onto phosphorylated Y1096, an alternative route to PI3K activation (Besset et al. 2000). SHC1 can also form a complex with GRB2:SOS leading to activation of the RAS-RAF-ERK pathway (Hayashi et al. 2000). However, mutation of Y1062 did not completely abolish activation of the RAS-RAF-ERK and PI3K-AKT pathways suggesting alternative signaling pathways (Ichihara et al. 2004). The adaptor protein FRS2 can bind phosphorylated Y1062 (Kurokawa et al. 2001, Melillo et al. 2001), competing with SHC1 (Lundgren et al. 2006). Differential signaling may be mediated by different compartments in the plasma membrane, as RET has been shown to interact with FRS2 in lipid rafts, but with SHC1 outside lipid rafts (Paratcha et al. 2001).<br><br>Many other proteins have been shown to bind and/or become activated via Y1062. Docking protein 1 (DOK1), 2, 4, 5, and 6 adaptor proteins all interact with phosphorylated Y1062 (Grimm et al. 2001; Crowder et al. 2004; Kurotsuchi et al. 2010). Other suggested RET interactors include Mitogen-activated protein kinase 7 (MAPK7, BMK1) (Hayashi et al. 2001), SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) (Schuetz et al. 2004), Insulin receptor substrate-2 (IRS2) (Hennige et al. 2000), SHC-transforming protein 3 (SHC3) (Pelicci et al. 2002), Protein kinase C alpha (PKCA) (Andreozzi et al. 2003) and PDZ and LIM domain protein 7 (Enigma, PDLIM7) (Durick et al. 1996). PDLIM7 and SHANK3 bind Y1062 regardless of its phosphorylation state.<br><br><br>Rap1GAP can bind phosphorylated Y981 to suppress GDNF-induced activation of ERK and neurite outgrowth (Jiao et al. 2011). <br><br>Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2) binds to phosphorylated Y687 and components of the Y1062 associated signaling complex, contributing to activation of PI3K/AKT and promoting survival and neurite outgrowth in primary neurons (Besset et al. 2000, Perrinjaquet et al. 2010).<br> <br>It is unclear how RET activates the p38MAPK, JNK, and ERK5 signaling pathways (Ichihara et al. 2004). To simplify the representation of RET signaling, all RET tyrosines known to be involved in signalling are phosphorylated in this event.Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88538181Reactome DB_ID: 11359230cytosolGO0005829ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 885416012x p-5Y-RET:GDNF:GFRA complexes [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexesConverted from EntitySet in ReactomeReactome DB_ID: 88557462p-5Y-RET:GFRA:GDNF complexes [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome Database ID Release 758854160Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854160ReactomeR-HSA-88541601Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854160.1Reactome DB_ID: 2937030ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 8853818GO0004714GO molecular functionReactome Database ID Release 758854772Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854772Reactome Database ID Release 758853792Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853792ReactomeR-HSA-88537922Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853792.210430490Pubmed1999Differential signaling of glial cell line-derived neurothrophic factor and brain-derived neurotrophic factor in cultured ventral mesencephalic neuronsFeng, LWang, C YJiang, HOho, CDugich-Djordjevic, MMei, LLu, BNeuroscience 93:265-739478934Pubmed1998Signal transduction pathways activated by RET oncoproteins in PC12 pheochromocytoma cellsXing, SFurminger, T LTong, QJhiang, S MJ. Biol. Chem. 273:4909-148662982Pubmed1996Mitogenic signaling by Ret/ptc2 requires association with enigma via a LIM domainDurick, KWu, R YGill, G NTaylor, S SJ. Biol. Chem. 271:12691-416847065Pubmed2006Engineering the recruitment of phosphotyrosine binding domain-containing adaptor proteins reveals distinct roles for RET receptor-mediated cell survivalLundgren, T KalleScott, Rizaldy PSmith, MatthewPawson, TErnfors, PatrikJ. Biol. Chem. 281:29886-9623378586Pubmed2013Structure and physiology of the RET receptor tyrosine kinaseIbáñez, Carlos FCold Spring Harb Perspect Biol 5:11360177Pubmed2001Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transductionKurokawa, KIwashita, TMurakami, HHayashi, HKawai, KTakahashi, MOncogene 20:1929-3811237712Pubmed2001Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutationHayashi, YIwashita, TMurakamai, HKato, YKawai, KKurokawa, KTohnai, IUeda, MTakahashi, MBiochem. Biophys. Res. Commun. 281:682-920682772Pubmed2010Protein-tyrosine phosphatase SHP2 contributes to GDNF neurotrophic activity through direct binding to phospho-Tyr687 in the RET receptor tyrosine kinasePerrinjaquet, MauriceVilar, MarçalIbáñez, Carlos FJ. Biol. Chem. 285:31867-7520210798Pubmed2010Analysis of DOK-6 function in downstream signaling of RET in human neuroblastoma cellsKurotsuchi, AiMurakumo, YoshikiJijiwa, MayumiKurokawa, KeiItoh, YasutomoKodama, YoshinoriKato, TakuyaEnomoto, AAsai, NaoyaTerasaki, HirokoTakahashi, MasahideCancer Sci. 101:1147-5510995764Pubmed2000Signaling complexes and protein-protein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinaseBesset, VScott, R PIbáñez, C FJ. Biol. Chem. 275:39159-6617036197Pubmed2006RET and neuroendocrine tumorsMurakumo, YoshikiJijiwa, MayumiAsai, NaoyaIchihara, MasatoshiTakahashi, MasahidePituitary 9:179-9210531419Pubmed1999Receptors of the glial cell line-derived neurotrophic factor family of neurotrophic factors signal cell survival through the phosphatidylinositol 3-kinase pathway in spinal cord motoneuronsSoler, R MDolcet, XEncinas, MEgea, JBayascas, J RComella, J XJ. Neurosci. 19:9160-920877310Pubmed2011Rap1GAP interacts with RET and suppresses GDNF-induced neurite outgrowthJiao, LiZhang, YHu, ChunWang, Yong-GangHuang, AijunHe, ChengCell Res. 21:327-3714711813Pubmed2004Identification of RET autophosphorylation sites by mass spectrometryKawamoto, YoshiyukiTakeda, KozueOkuno, YusukeYamakawa, YoshinoriIto, YasutomoTaguchi, RyoKato, MasashiSuzuki, HaruhikoTakahashi, MasahideNakashima, IzumiJ. Biol. Chem. 279:14213-2410448070Pubmed1999Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by ret with the MEN 2B mutationMurakami, HIwashita, TAsai, NShimono, YIwata, YKawai, KTakahashi, MBiochem. Biophys. Res. Commun. 262:68-7515013219Pubmed2004RET and neuroendocrine tumorsIchihara, MasatoshiMurakumo, YoshikiTakahashi, MasahideCancer Lett. 204:197-21115569713Pubmed2004The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cellsSchuetz, GunnarRosário, MartaGrimm, JanBoeckers, Tobias MGundelfinger, Eckart DBirchmeier, WalterJ. Cell Biol. 167:945-529627110Pubmed1998Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKS): evidence for a divergence of the ERKs and JNKs pathways induced by RetChiariello, MVisconti, RCarlomagno, FMelillo, R MBucci, Cde Franciscis, VFox, G MJing, SCoso, O AGutkind, J SFusco, ASantoro, MOncogene 16:2435-4511000521Pubmed2000Ret oncogene signal transduction via a IRS-2/PI 3-kinase/PKB and a SHC/Grb-2 dependent pathway: possible implication for transforming activity in NIH3T3 cellsHennige, A MLammers, RArlt, DHöppner, WStrack, VNiederfellner, GSeif, F JHäring, Hans-UlrichKellerer, MMol. Cell. Endocrinol. 167:69-768570170Pubmed1995Ret receptor tyrosine kinase activates extracellular signal-regulated kinase 2 in SK-N-MC cellsvan Weering, D HMedema, J Pvan Puijenbroek, ABurgering, B MBaas, P DBos, J LOncogene 11:2207-1412771945Pubmed2003Protein kinase Calpha activation by RET: evidence for a negative feedback mechanism controlling RET tyrosine kinaseAndreozzi, FrancescoMelillo, Rosa MarinaCarlomagno, FrancescaOriente, FrancescoMiele, ClaudiaFiory, FrancescaSantopietro, StefaniaCastellone, Maria DomenicaBeguinot, FrancescoSantoro, MassimoFormisano, PietroOncogene 22:2942-911182089Pubmed2001Released GFRalpha1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid raftsParatcha, GLedda, FBaars, LCoulpier, MBesset, VAnders, JScott, RIbáñez, C FNeuron 29:171-8412242309Pubmed2002The neuron-specific Rai (ShcC) adaptor protein inhibits apoptosis by coupling Ret to the phosphatidylinositol 3-kinase/Akt signaling pathwayPelicci, GiulianaTroglio, FlaviaBodini, AlessandraMelillo, Rosa MarinaPettirossi, ValentinaCoda, LauraDe Giuseppe, AntonioSantoro, MassimoPelicci, PGMol. Cell. Biol. 22:7351-638798576Pubmed1996Glial cell line-derived neurotrophic factor signals through the RET receptor and activates mitogen-activated protein kinaseWorby, C AVega, Q CZhao, YChao, H HSeasholtz, A FDixon, J EJ. Biol. Chem. 271:23619-2215286081Pubmed2004Dok-6, a Novel p62 Dok family member, promotes Ret-mediated neurite outgrowthCrowder, Robert JEnomoto, HidekiYang, MaoJohnson, Eugene MMilbrandt, JeffreyJ. Biol. Chem. 279:42072-8111002419Pubmed2000Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factorHayashi, HIchihara, MIwashita, TMurakami, HShimono, YKawai, KKurokawa, KMurakumo, YImai, TFunahashi, HNakao, ATakahashi, MOncogene 19:4469-758995255Pubmed1997Glial cell line-derived neurotrophic factor induces Ret-mediated lamellipodia formationvan Weering, D HBos, J LJ. Biol. Chem. 272:249-549299438Pubmed1997Characterization of Ret-Shc-Grb2 complex induced by GDNF, MEN 2A, and MEN 2B mutationsOhiwa, MMurakami, HIwashita, TAsai, NIwata, YImai, TFunahashi, HTakagi, HTakahashi, MBiochem. Biophys. Res. Commun. 237:747-5110208419Pubmed1999Rho-dependent and -independent tyrosine phosphorylation of focal adhesion kinase, paxillin and p130Cas mediated by Ret kinaseMurakami, HIwashita, TAsai, NIwata, YNarumiya, STakahashi, MOncogene 18:1975-8210652352Pubmed2000Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathwaySegouffin-Cariou, CBillaud, MJ. Biol. Chem. 275:3568-7610409632Pubmed1999Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cellsTrupp, MScott, RWhittemore, S RIbáñez, C FJ. Biol. Chem. 274:20885-9411470823Pubmed2001Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiationGrimm, JSachs, MBritsch, SDi Cesare, SSchwarz-Romond, TAlitalo, KBirchmeier, WJ. Cell Biol. 154:345-5411390647Pubmed2001Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascadeMelillo, R MSantoro, MOng, S HBillaud, MFusco, AHadari, Y RSchlessinger, JLax, IMol. Cell. Biol. 21:4177-8714766744Pubmed2004Tyrosine 981, a novel ret autophosphorylation site, binds c-Src to mediate neuronal survivalEncinas, MarioCrowder, Robert JMilbrandt, JeffreyJohnson, Eugene MJ. Biol. Chem. 279:18262-98637703Pubmed1996Identification of tyrosine residues that are essential for transforming activity of the ret proto-oncogene with MEN2A or MEN2B mutationIwashita, TAsai, NMurakami, HMatsuyama, MTakahashi, MOncogene 12:481-72.7.11PKA phosphorylates RET:GDNF:GFRA dimerPKA phosphorylates RET:GDNF:GFRA dimerSerine (S) 696 in RET is phosphorylated by protein kinase A. Mutation of this serine almost completely inhibits the ability of RET to activate the small GTPase Rac1 and stimulate formation of cell lamellipodia (Fukuda et al. 2002). Homozygous knock-in mice carrying this mutation lacked enteric neurons in the distal colon, resulting from a migration defect of enteric neural crest cells (Asai et al. 2006). The effects of the S696 RET mutant could be alleviated by simultaneous mutation of Tyrosine-687 (Fukuda et al. 2002). Activation of PKA by forskolin was found to impair the recruitment of SHP2 to RET and negatively affect ligand-mediated neurite outgrowth (Perrinjaquet et al. 2010). Mutation of S696 enhanced SHP2 binding and eliminated the effect of forskolin on ligand-induced neurite outgrowth.Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88538181Reactome DB_ID: 1135926Reactome DB_ID: 885576012x p-S696-RET:GFRA:GDNF complexes [plasma membrane]2x p-S696-RET:GFRA:GDNF complexesConverted from EntitySet in ReactomeReactome DB_ID: 88557522p-S696-RET:GFRA:GDNF complexes [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome Database ID Release 758855760Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855760ReactomeR-HSA-88557602Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855760.2Reactome DB_ID: 293706PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 425833Protein kinase A catalytic subunit [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGO0004674GO molecular functionReactome Database ID Release 75426259Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426259Reactome Database ID Release 758854908Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854908ReactomeR-HSA-88549082Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854908.211886862Pubmed2002Novel mechanism of regulation of Rac activity and lamellipodia formation by RET tyrosine kinaseFukuda, ToshifumiKiuchi, KazutoshiTakahashi, MasahideJ. Biol. Chem. 277:19114-2117050626Pubmed2006Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cellsAsai, NaoyaFukuda, ToshifumiWu, ZaiqiEnomoto, APachnis, VassilisTakahashi, MasahideCostantini, FrankDevelopment 133:4507-162x p-5Y-RET:GDNF:GFRA complexes binds DOK1,DOK2,DOK4,DOK5,DOK62x p-5Y-RET:GDNF:GFRA complexes binds DOK1,DOK2,DOK4,DOK5,DOK6Docking protein 1 (DOK 1), 2, 4, 5, and 6 adaptor proteins all interact with RET at phosphorylated tyrosine-1062 (Y1062) (Grimm et al. 2001, Crowder et al. 2004, Kurotsuchi et al. 2010). <br><br>DOKs are adaptor proteins that can inhibit mitogen-activated protein kinase (MAPK) signaling, cell proliferation, and cellular transformation. DOK1 and 2 may exert their inhibitory effects by recruiting Ras GTPase-activating protein 1 (RASA1, RasGAP), which is a negative regulator of Ras signaling, but DOK2 can attenuate EGF receptor-induced MAP kinase activation without RASA1. DOK3 negatively regulates signaling by recruiting INPP5D and CSK (Grimm et al. 2001).<br><br>RET promotes neurite outgrowth of the rat pheochromocytoma cell line PC12 via Y1062. RET-DOK4/5 fusion proteins induced ligand-dependent axonal outgrowth of PC12 cells, while RET-DOK2 fusions did not. DOK4/5 do not associate with RASA1 or NCK, and enhance RET-dependent activation of MAPK (Grimm et al. 2001).Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Converted from EntitySet in ReactomeReactome DB_ID: 88556191DOK1,DOK2,DOK4,DOK5,DOK6 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDOK5 [cytosol]DOK6 [cytosol]DOK2 [cytosol]DOK1 [cytosol]DOK4 [cytosol]UniProtQ9P104UniProtQ6PKX4UniProtO60496UniProtQ99704UniProtQ8TEW6Reactome DB_ID: 88541601Reactome DB_ID: 885557312x p-5Y-RET:GDNF:GFRA complexes:DOK1,DOK2,DOK4,DOK5,DOK6 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:DOK1,DOK2,DOK4,DOK5,DOK6Converted from EntitySet in ReactomeReactome DB_ID: 88556191Reactome DB_ID: 88541601Reactome Database ID Release 758855573Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855573ReactomeR-HSA-88555732Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855573.2Reactome Database ID Release 758855617Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855617ReactomeR-HSA-88556172Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855617.22x p-5Y-RET:GDNF:GFRA complexes bind RET interactors2x p-5Y-RET:GDNF:GFRA complexes bind RET interactorsOther RET interactors that may have a role in RET signaling include Mitogen-activated protein kinase 7 (MAPK7, BMK1) (Hayashi et al. 2001), SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) (Schuetz et al. 2004), Insulin receptor substrate-2 (IRS2) (Hennige et al. 2000), SHC-transforming protein 3 (SHC3) (Pelicci et al. 2002), Protein kinase C alpha (PKCA) (Andreozzi et al. 2003) and PDZ and LIM domain protein 7 (Enigma, PDLIM7) (Durick et al. 1996). PDLIM7 and SHANK3 bind Tyrosine-1062 regardless of its phosphorylation state.Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88541601Converted from EntitySet in ReactomeReactome DB_ID: 88559131RET interactors [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitySHC3 [cytosol]SHANK3 [cytosol]PDLIM7 [cytosol]MAPK7 [cytosol]PRKCA [cytosol]IRS2 [cytosol]UniProtQ92529UniProtQ9BYB0UniProtQ9NR12UniProtQ13164UniProtP17252UniProtQ9Y4H2Reactome DB_ID: 885591412x p-5Y-RET:GDNF:GFRA complexes:RET interactors [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:RET interactorsReactome DB_ID: 88541601Converted from EntitySet in ReactomeReactome DB_ID: 88559131Reactome Database ID Release 758855914Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855914ReactomeR-HSA-88559142Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855914.2Reactome Database ID Release 758855915Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855915ReactomeR-HSA-88559152Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855915.22x p-5Y-RET:GDNF:GFRA complexes bind FRS22x p-5Y-RET:GDNF:GFRA complexes bind FRS2RET can bind FRS2, via phosphotyrosine-1062 (p-Y1062) (Kurokawa et al. 2001, Meillo et al. 2001). FRS2 competes with SHC1 for p-Y1062 binding (Lundgren et al. 2006). RET has been reported to associate with FRS2, instead of SHC1, when associated with lipid rafts (Paratcha et al. 2001).Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88541601Reactome DB_ID: 1709631UniProt:Q8WU20 FRS2FRS2FRS2FUNCTION Adapter protein that links activated FGR and NGF receptors to downstream signaling pathways. Plays an important role in the activation of MAP kinases and in the phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, in response to ligand-mediated activation of FGFR1. Modulates signaling via SHC1 by competing for a common binding site on NTRK1.SUBUNIT Part of a complex containing FRS2, GRB2, GAB1, PIK3R1 and SOS1. Part of a complex containing GRB2 and CBL. Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Binds RET (By similarity). Binds ALK, FGFR1, CKS2, MAPK1/ERK2, MAPK3/ERK1 and SRC. The tyrosine-phosphorylated protein binds the SH2 domains of GRB2 and PTPN11. Interacts with NTRK1, NTRK2 and NTRK3 (phosphorylated upon ligand-binding).TISSUE SPECIFICITY Highly expressed in heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis.PTM Phosphorylated by ULK2 in vitro (By similarity). Phosphorylated on tyrosine residues upon stimulation by NGF or FGF2. Phosphorylated on tyrosine residues by activated ALK and FGFR1. Phosphorylated on tyrosine residues upon activation of FGFR2 and FGFR3. Phosphorylated on threonine residues by MAP kinases; this inhibits tyrosine phosphorylation, and thereby down-regulates FRS2-mediated activation of MAP kinases.PTM Ubiquitinated when tyrosine phosphorylated and in a complex with GRB2. The unphosphorylated form is not subject to ubiquitination (By similarity).UniProtQ8WU201EQUAL508EQUALReactome DB_ID: 885557912x p-5Y-RET:GDNF:GFRA complexes:FRS2 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:FRS2Reactome DB_ID: 88541601Reactome DB_ID: 17096311EQUAL508EQUALReactome Database ID Release 758855579Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855579ReactomeR-HSA-88555792Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855579.2Reactome Database ID Release 758855564Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855564ReactomeR-HSA-88555643Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855564.32x p-5Y-RET:GDNF:GFRA complexes bind SHC12x p-5Y-RET:GDNF:GFRA complexes bind SHC1GDNF stimulation of neuronal cells induces the assembly of a large protein complex containing RET, GRB2 and tyrosine-phosphorylated SHC1, p85 subunit of (PI3K), GAB2 (GAB1 in Hayashi et al. 2000) and Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP-2) (Besset et al. 2000). RET binds SHC1 via phosphorylated tyrosine-1062 (Asai et al. 1996, Arighi et al. 1997).Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88541601Reactome DB_ID: 746801UniProt:P29353 SHC1SHC1SHC1SHCASHCFUNCTION Signaling adapter that couples activated growth factor receptors to signaling pathways. Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Isoform p46Shc and isoform p52Shc, once phosphorylated, couple activated receptor tyrosine kinases to Ras via the recruitment of the GRB2/SOS complex and are implicated in the cytoplasmic propagation of mitogenic signals. Isoform p46Shc and isoform p52Shc 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 (By similarity). Participates in signaling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis.SUBUNIT Interacts with CPNE3; this interaction may mediate the binding of CPNE3 with ERBB2 (PubMed:20010870). 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 CD3T and DDR2. Interacts with the N-terminal region of APS. Interacts with phosphorylated LRP1 and IRS4. Interacts with INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with TRIM31. Interacts with PTPN6/SHP (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTT (By similarity). Interacts with ALK, GAB2, GRB7 and KIT. Interacts with FLT4 (tyrosine-phosphorylated). Interacts with EPHB1 and GRB2; activates the MAPK/ERK cascade to regulate cell migration. Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with ERBB4. Interacts with TEK/TIE2 (tyrosine-phosphorylated). Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a phosphotyrosine-dependent manner. Interacts with PTK2/FAK1. 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). Interacts (via PID domain) with PEAK1 (when phosphorylated at 'Tyr-1188') (PubMed:23846654). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 UL46.TISSUE SPECIFICITY Widely expressed. Expressed in neural stem cells but absent in mature neurons.DOMAIN In response to a variety of growth factors, isoform p46Shc and isoform p52Shc bind to phosphorylated Trk 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 of the Trk receptors. Isoform p46Shc 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 (By similarity).PTM Phosphorylated by activated epidermal growth factor receptor. Phosphorylated in response to FLT4 and KIT signaling. Isoform p46Shc 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 (By similarity). Tyrosine phosphorylated in response to FLT3 signaling (By similarity). Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity). Tyrosine phosphorylated by ligand-activated ALK. Tyrosine phosphorylated by ligand-activated PDGFRB. Tyrosine phosphorylated by TEK/TIE2. May be tyrosine phosphorylated by activated PTK2/FAK1; tyrosine phosphorylation was seen in an astrocytoma biopsy, where PTK2/FAK1 kinase activity is high, but not in normal brain tissue. Isoform p52Shc dephosphorylation by PTPN2 may regulate interaction with GRB2.UniProtP293531EQUAL583EQUALReactome DB_ID: 885440012x p-5Y-RET:GDNF:GFRA complexes:SHC1 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:SHC1Reactome DB_ID: 88541601Reactome DB_ID: 7468011EQUAL583EQUALReactome Database ID Release 758854400Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854400ReactomeR-HSA-88544002Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854400.2Reactome Database ID Release 758853737Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853737ReactomeR-HSA-88537372Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853737.28663426Pubmed1996A mutation at tyrosine 1062 in MEN2A-Ret and MEN2B-Ret impairs their transforming activity and association with shc adaptor proteinsAsai, NMurakami, HIwashita, TTakahashi, MJ. Biol. Chem. 271:17644-99047384Pubmed1997Identification of Shc docking site on Ret tyrosine kinaseArighi, EAlberti, LTorriti, FGhizzoni, SRizzetti, M GPelicci, GPasini, BBongarzone, IPiutti, CPierotti, M ABorrello, M GOncogene 14:773-82SHC1 in the RET complex is phosphorylatedSHC1 in the RET complex is phosphorylatedGDNF stimulation of neuronal cells induces the assembly of a large protein complex containing RET, GRB2 and tyrosine-phosphorylated SHC1, p85 subunit of (PI3K), GAB2 (GAB1 in Hayashi et al. 2000), and Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP-2) (Besset et al. 2000). Based on the mechanism of SHC1 activation in other receptor systems (Gu et al. 2000) it is likely that SHC1 tyrosine (Y) phosphorylation occurs as a consequence of RET binding and is required for subsequent events. GRB2 binding to SHC1 requires phosphorylation of Y349, Y350 and/or Y427 (Gu et al. 2000). Mutation of RET Y1062, which binds SHC1 to initiate recruitment of GRB2-GAB-p85, did not completely abolish the activation of RAS-RAF-ERK and PI3K-AKT (Besset et al. 2000), suggesting there are alternative pathways that do not utilize SHC1. RET has been shown to bind GRB2 directly, via Y1096 (Alberti et al. 1998, Besset et al. 2000). <br><br>It has not been established whether SHC1 associates with RET in phosphorylated form or is phosphorylated after binding, and the identity of the kinase is unknown, hence this is represented as an uncertain event.Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88544001Reactome DB_ID: 885498012x p-5Y-RET:GDNF:GFRA complexes:p-Y349,Y350,Y427-SHC1 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:p-Y349,Y350,Y427-SHC1Reactome DB_ID: 88541601Reactome DB_ID: 9123211O4'-phospho-L-tyrosine at 427427EQUALO4'-phospho-L-tyrosine [MOD:00048]O4'-phospho-L-tyrosine at 349349EQUALO4'-phospho-L-tyrosine at 350350EQUAL1EQUAL583EQUALReactome Database ID Release 758854980Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854980ReactomeR-HSA-88549801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854980.1Reactome Database ID Release 758854981Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854981ReactomeR-HSA-88549812Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854981.29764818Pubmed1998Grb2 binding to the different isoforms of Ret tyrosine kinaseAlberti, LBorrello, M GGhizzoni, STorriti, FRizzetti, M GPierotti, M AOncogene 17:1079-8710982827Pubmed2000New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathwayGu, HMaeda, HMoon, JJLord, JDYoakim, MNelson, BHNeel, BGMol Cell Biol 20:7109-202x p-5Y-RET:GDNF:GFRA complexes:p-Y349,Y350,Y427-SHC1 binds GRB2-1:SOS12x p-5Y-RET:GDNF:GFRA complexes:p-Y349,Y350,Y427-SHC1 binds GRB2-1:SOS1RET has been shown to bind GRB2 indirectly via SHC (Ohiwa et al. 1997). GRB2 is found in a complex with SOS1 in unstimulated cells (Hayashi et al. 2000).<br><br>GDNF stimulation of neuronal cells induces the assembly of a large protein complex containing RET, GRB2 and tyrosine-phosphorylated SHC, p85 subunit of (PI3K), GAB2 (GAB1 in Hayashi et al. 2000) and Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP-2) (Besset et al. 2000). This suggests that at least two distinct RET-SHC protein complexes can assemble via phosphorylated Tyrosine (Y) 1062, one involving GRB2:SOS1 leads to activation of the Ras/Erk pathway, another involving GRB1/2, GAB2 and PI3K leads to the PI3K/Akt pathway. This latter complex can also assemble directly onto phosphorylated Y1096 (Besset et al. 2000). <br><br>RET can activate the RAS-RAF-ERK signaling pathway (van Weering et al. 1995, Ohiwa et al. 1997, van Weering & Bos 1997, Trupp et al. 1999, Hayashi et al. 2000). RAS signaling is markedly impaired by mutations of RET Y1062 (Hayashi et al. 2000). RET RAS signaling and the effect of the Y1062 mutation are believed to be mediated by RET complexes involving GRB2:SOS, well known as mediators of signaling to RAS in other receptor systems (Ravichandran 2001). Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 1097971GRB2-1:SOS1 [cytosol]GRB2-1:SOS1Reactome DB_ID: 746861UniProt:P62993-1 GRB2GRB2ASHGRB2FUNCTION Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.FUNCTION Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.SUBUNIT Associates (via SH2 domain) with activated EGF and PDGF receptors (tyrosine phosphorylated) (PubMed:10026169, PubMed:19836242). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect (By similarity). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, IRS1, IRS4, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains (PubMed:8388384, PubMed:8491186, PubMed:9553137, PubMed:11433379). It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1 (PubMed:8493579, PubMed:7664271). Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1 (PubMed:7664271). Interacts with phosphorylated MET (PubMed:11063574, PubMed:11827484). Interacts with phosphorylated TOM1L1 (By similarity). Interacts with the phosphorylated C-terminus of SH2B2 (PubMed:9233773). Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation (By similarity) (PubMed:9489702, PubMed:12359715, PubMed:12486104, PubMed:12514734). Interacts with NISCH, PTPNS1 and REPS2 (PubMed:9062191, PubMed:9422736, PubMed:11912194). Interacts with syntrophin SNTA1 (By similarity). Interacts (via SH3 domains) with REPS1 (By similarity). Interacts (via SH3 domains) with PIK3C2B (PubMed:11533253). Interacts with CBL and CBLB (PubMed:10022120, PubMed:10086340). Interacts with AJUBA and CLNK (By similarity). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2 (PubMed:8723348, PubMed:9108392, PubMed:9484780, PubMed:10942756, PubMed:12171928). Interacts with PTPN11 (By similarity). Interacts with PRNP (By similarity). Interacts with RALGPS1 (PubMed:10747847). Interacts with HCST (PubMed:16582911). Interacts with KDR (By similarity). Interacts with FLT1 (tyrosine-phosphorylated) (By similarity). Interacts with GAPT and PTPRE (PubMed:10980613, PubMed:18559951). Interacts (via SH2 domain) with KIF26A (PubMed:19914172). Interacts (via SH3 2) with GAB2 (PubMed:19523899). Interacts with ADAM15 (PubMed:18296648). Interacts with THEMIS2 (By similarity). Interacts (via SH2 domain) with AXL (phosphorylated) (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with KIT (phosphorylated) (PubMed:15526160, PubMed:16129412). Interacts with PTPRJ and BCR (PubMed:12475979, PubMed:15302586). Interacts with PTPN23 (PubMed:21179510). Interacts with FLT4 (tyrosine phosphorylated) (PubMed:15102829). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:8798570, PubMed:12925710). Part of a complex including TNK2, GRB2, LTK and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2 (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:8262059). Interacts with ERBB4 (PubMed:10867024). Interacts with NTRK1 (phosphorylated upon ligand-binding) (PubMed:15488758). Interacts with PTK2/FAK1 (tyrosine phosphorylated) (PubMed:9148935). Interacts with PTK2B/PYK2 (tyrosine phosphorylated) (PubMed:20521079). Isoform 1: Interacts (via SH2-domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-69' (PubMed:21930792). Interacts (via SH3 domains) with GAREM1 isoform 1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation (PubMed:19509291). Interacts with DAB2 (By similarity). Interacts with TESPA1 (PubMed:22561606). Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1 (By similarity). Interacts with CD28 (PubMed:24098653). Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA (By similarity). Interacts with ASAP3 (phosphorylated form) (PubMed:22027826). Interacts (via SH2 domain) with PTPRH (phosphorylated form) (By similarity). Interacts with PTPRO (phosphorylated form) (By similarity). Interacts with PTPRB (phosphorylated form) (By similarity). Interacts (via SH3 domain 2) with PRR14 (via proline-rich region) (PubMed:27041574). Interacts with FCRL6 (tyrosine phosphorylated form) (PubMed:20933011). Interacts with RHEX (via tyrosine-phosphorylated form) (PubMed:25092874). Interacts with DENND2B (PubMed:29030480). Interacts (via SH3 domain) with ZDHHC19 (via SH3-binding motif); leading to recruit STAT3 (PubMed:31462771).SUBUNIT (Microbial infection) Interacts (via SH3 domain) with hepatitis E virus/HEV ORF3 protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus/HCV protein NS5A via its SH3 domains.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL46.DOMAIN The SH3 domains mediate interaction with RALGPS1 and SHB.SIMILARITY Belongs to the GRB2/sem-5/DRK family.UniProtP62993-11EQUAL217EQUALReactome DB_ID: 648471UniProt:Q07889 SOS1SOS1SOS1FUNCTION Promotes the exchange of Ras-bound GDP by GTP (PubMed:8493579). Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (PubMed:17339331). 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 (By similarity).SUBUNIT Interacts (via C-terminus) with GRB2 (via SH3 domain) (PubMed:8493579, PubMed:7664271). Forms a complex with phosphorylated MUC1 and GRB2 (via its SH3 domains) (PubMed:7664271). Interacts with phosphorylated LAT2 (PubMed:12486104). Interacts with NCK1 and NCK2 (PubMed:10026169). Part of a complex consisting of ABI1, EPS8 and SOS1 (By similarity). Interacts (Ser-1134 and Ser-1161 phosphorylated form) with YWHAB and YWHAE (PubMed:22827337).TISSUE SPECIFICITY Expressed in gingival tissues.PTM Phosphorylation at Ser-1134 and Ser-1161 by RPS6KA3 create YWHAB and YWHAE binding sites and which contribute to the negative regulation of EGF-induced MAPK1/3 phosphorylation.UniProtQ078891EQUAL1333EQUALReactome Database ID Release 75109797Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109797ReactomeR-HSA-1097973Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-109797.3Reactome DB_ID: 88549801Reactome DB_ID: 885439912x p-5Y-RET:GDNF:GFRA complexes:p-Y349,Y350,Y427-SHC1:GRB2-1:SOS1 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:p-Y349,Y350,Y427-SHC1:GRB2-1:SOS1Reactome DB_ID: 1097971Reactome DB_ID: 88549801Reactome Database ID Release 758854399Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854399ReactomeR-HSA-88543991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854399.1Reactome Database ID Release 758853734Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853734ReactomeR-HSA-88537343Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853734.311607835Pubmed2001Signaling via Shc family adapter proteinsRavichandran, K SOncogene 20:6322-302x p-5Y-RET:GDNF:GFRA complexes bind GRB2-1:SOS12x p-5Y-RET:GDNF:GFRA complexes bind GRB2-1:SOS1RET has been shown to bind GRB2 directly, via Tyrosine-1096 (Y1096) (Alberti et al. 1998, Besset et al. 2000). GRB2 is found in a complex with SOS1 in unstimulated cells (Hayashi et al. 2000).<br><br>GDNF stimulation of neuronal cells induces the assembly of a large protein complex containing RET, GRB2 and tyrosine-phosphorylated SHC1, p85 subunit of (PI3K), GAB2 (GAB1 in Hayashi et al. 2000) and Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP-2) (Besset et al. 2000). This suggests that at least two distinct RET-SHC1 protein complexes can assemble via phosphorylated Y1062, one involving GRB2 and SOS1 leads to activation of the RAS-RAF-ERK pathway, another involving GRB2, GAB2 and p85 leads to the PI3K-AKT pathway. This latter complex can also assemble directly onto phosphorylated Y1096 (Besset et al. 2000).<br><br>RET can activate the RAS-RAF-ERK signaling pathway (van Weering et al. 1995, Ohiwa et al. 1997, van Weering & Bos 1997, Trupp et al. 1999, Hayashi et al. 2000). RAS signaling is markedly impaired by mutations of RET Y1062 (Hayashi et al. 2000). RET RAS signaling and the effect of the Y1062 mutation are believed to be mediated by RET complexes involving GRB2:SOS1, well known as mediators of signaling to RAS in other receptor systems (Ravichandran 2001). Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88541601Reactome DB_ID: 1097971Reactome DB_ID: 885490312x p-5Y-RET:GDNF:GFRA complexes:GRB2-1:SOS1 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:GRB2-1:SOS1Reactome DB_ID: 88541601Reactome DB_ID: 1097971Reactome Database ID Release 758854903Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854903ReactomeR-HSA-88549031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854903.1Reactome Database ID Release 758854899Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854899ReactomeR-HSA-88548992Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854899.2p-5Y-RET complexes bind GRB2p-5Y-RET complexes bind GRB2GDNF stimulation of neuronal cells induces the assembly of a large protein complex containing RET, GRB2 and tyrosine-phosphorylated SHC1, p85 subunit of (PI3K), GAB2 (GAB1 in Hayashi et al. 2000), and Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP-2) (Besset et al. 2000). GAB1 was found in complexes with GRB2 only after GDNF treatment (Hayashi et al. 2000). This contrasts with reports in other systems where GAB2-GRB2 were reported to constitutively associate (Gu et al. 1998). The likely order of recruitment to RET is SHC1, GRB2, GAB1/2, similar to the signaling mechanism of the Interleukin-3 receptor (Gu et al. 2000) and many others (Adams et al. 2012).Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 7468611EQUAL217EQUALConverted from EntitySet in ReactomeReactome DB_ID: 88549001p-5Y-RET:GDNF:GFRA complexes with and without p-SHC1 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityConverted from EntitySet in ReactomeReactome DB_ID: 885490712x p-5Y-RET:GDNF:GFRA complexes with, without p-SHC1:GRB2-1 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome Database ID Release 758853793Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853793ReactomeR-HSA-88537932Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853793.222871571Pubmed2012GAB2--a scaffolding protein in cancerAdams, Sarah JAydin, Iraz TCelebi, Julide TMol. Cancer Res. 10:1265-709885561Pubmed1998Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activationGu, HPratt, JCBurakoff, SJNeel, BGMol Cell 2:729-40p-5Y-RET-GRB2-containing complexes bind GAB1,GAB2p-5Y-RET-GRB2-containing complexes bind GAB1,GAB2Grb-associated binder (GAB) proteins are a family of docking proteins that transduce cellular signals between receptors and intracellular downstream effectors (Ding et al. 2015). When phosphorylated by protein-tyrosine kinases, GABs can recruit several Src homology-2 (SH2) domain-containing proteins, including Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2), the p85 subunit of phosphoinositide-3 kinase (p85-PI3K), phospholipase C-gamma 1 (PLCG1), CRK and GAB-associated Cdc42/Rac GTPase-activating protein (ARHGAP32, GC-GAP). These interactions lead to various downstream signals involved in cell growth, differentiation, migration and apoptosis.<br><br>GDNF stimulation of neuronal cells induces the assembly of a large protein complex containing RET, GRB2 and tyrosine-phosphorylated SHC1, p85-PI3K, GAB2 (GAB1 in Hayashi et al. 2000) and PTPN11 (Besset et al. 2000). GAB1 was found in complexes with GRB2 only after GDNF treatment (Hayashi et al. 2000). This contrasts with reports that GAB2 constitutively associates with GRB2 (Gu et al. 1998). <br><br>The likely order of recruitment to RET is SHC1, GRB2, GAB1/2, p85-PI3K, similar to the signaling mechanism of the Interleukin-3 receptor (Gu et al. 2000) and many others (Adams et al. 2012, Ding et al. 2015). As the order of RET complex formation is not firmly established, GAB binding is shown as an uncertain event.Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Converted from EntitySet in ReactomeReactome DB_ID: 88549071Converted from EntitySet in ReactomeReactome DB_ID: 88550921GAB1,GAB2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGAB1 [cytosol]GAB2 [cytosol]UniProtQ13480UniProtQ9UQC2Reactome DB_ID: 885509012x p-5Y-RET:GDNF:GFRA complexes with, without p-SHC1:GRB2-1:GAB1,GAB2 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes with, without p-SHC1:GRB2-1:GAB1,GAB2Converted from EntitySet in ReactomeReactome DB_ID: 88549071Converted from EntitySet in ReactomeReactome DB_ID: 88550921Reactome Database ID Release 758855090Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855090ReactomeR-HSA-88550902Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855090.2Reactome Database ID Release 758854897Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854897ReactomeR-HSA-88548972Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854897.226095858Pubmed2015Structure and function of Gab2 and its role in cancer (Review)Ding, Chen-BoYu, Wei-NaFeng, Ji-HongLuo, Jun-MinMol Med Rep 12:4007-14GAB in p-5Y-RET:GDNF:GFRA complexes is phosphorylatedGAB in p-5Y-RET:GDNF:GFRA complexes is phosphorylatedGrb2-associated-binder (GAB) family signaling is mediated by tyrosine phosphorylation. GAB1-3 all have an N-terminal pleckstrin homology (PH) domain, proline-rich motifs, and multiple potential tyrosyl and seryl/threonyl phosphorylation sites (Gu & Neel 2003, Liu & Rohrschneider 2002). GAB2 has several docking sites for SH2 domain-containing molecules, including tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP-2) and the p85 subunit of phosphatidylinositol 3-kinase (p85-PI3K) (Ding et al. 2015). Similarly, GAB1 associates with PTPN11 and p85-PI3K; these interactions are considered essential for GAB1 activation of extracellular signal-regulated kinase (ERK)1/2 and PI3K-AKT, respectively (Wang et al. 2015).<br><br>GAB2 has three tyrosine (Y) residues, Y452, Y476 and Y584, that are binding sites for p85-PI3K (Crouin et al. 2001, Maus et al. 2009) and two more (Y614 and Y643) that interact with the SH2 domains of PTPN11 (Gu et al. 1998, Crouin et al. 2001, Arnaud et al. 2004). GAB1 also becomes tyrosine phosphorylated when transducing signals from receptor tyrosine kinases to p85 (Holgado-Madruga et al. 1997, Mattoon et al. 2004). There are three potential binding sites for p85 on GAB1 (Y447, Y472, and Y589) (Holgado-Madruga et al. 1997). GAB1 Y627 and Y659 appear to link it to PTPN11; GAB1 mutants that are unable to bind PTPN11 do not activate ERK (Schaeper et al. 2000, Cunnick et al. 2000, Sármay et al. 2006).<br><br>PI3K activation produces membrane-associated PI(3,4,5)P3, which facilitates membrane association of the PH domain of GAB, enhancing its recruitment (Zhang et al. 2009) in a positive feed-back loop. The kinases responsible for GAB phosphorylation are cell-type and receptor specific (Maus et al. 2009). <br><br>GDNF stimulation of neuronal cells induces the assembly of a complex containing RET, GRB2 and tyrosine-phosphorylated SHC, p85 subunit of (PI3K), GAB2 (GAB1 in Hayashi et al. 2000) and PTPN11 (SHP2) (Besset et al. 2000). GAB1 was found in complexes with GRB2 only after GDNF treatment (Hayashi et al. 2000). The likely order of recruitment to RET is SHC, GRB2, GAB1/2, p85 and/or PTPN11, similar to the signaling mechanism of the Interleukin-3 receptor (Gu et al. 2000) and others (Adams et al. 2012, Ding et al. 2015). It is likely, though not demonstrated, that GAB1/2 become tyrosine phosphorylated after binding GRB2 in the RET receptor complex. The kinase responsible is unclear. As the order of GAB binding and phosphorylation, and the identity of the kinase responsible for GAB phosphorylation have not been demonstrated, GAB phosphorylation in the RET complex is shown as an uncertain event.Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 1135925Reactome DB_ID: 88550901Reactome DB_ID: 293705Reactome DB_ID: 885530212x p-5Y-RET:GDNF:GFRA complexes with, without p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes with, without p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2Converted from EntitySet in ReactomeReactome DB_ID: 88549071Converted from EntitySet in ReactomeReactome DB_ID: 88552961p-5Y-GAB1,p-5Y-GAB2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-5Y-GAB2 [cytosol]p-5Y-GAB1 [cytosol]Reactome Database ID Release 758855302Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855302ReactomeR-HSA-88553022Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855302.2Reactome Database ID Release 758853774Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853774ReactomeR-HSA-88537742Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853774.210788507Pubmed2000Requirement of SHP2 binding to Grb2-associated binder-1 for mitogen-activated protein kinase activation in response to lysophosphatidic acid and epidermal growth factorCunnick, J MDorsey, J FMuñoz-Antonia, TMei, LWu, JJ. Biol. Chem. 275:13842-812628344Pubmed2003The "Gab" in signal transductionGu, HaihuaNeel, Benjamin GTrends Cell Biol. 13:122-3011943184Pubmed2002The gift of GabLiu, YanRohrschneider, Larry RFEBS Lett. 515:1-716386802Pubmed2006The multiple function of Grb2 associated binder (Gab) adaptor/scaffolding protein in immune cell signalingSármay, GabriellaAngyal, AdriennKertész, AkosMaus, MátéMedgyesi, DávidImmunol. Lett. 104:76-8218950707Pubmed2009Grb2 associated binder 2 couples B-cell receptor to cell survivalMaus, MátéMedgyesi, DávidKövesdi, DorottyaCsuka, DorottyaKoncz, GáborSármay, GabriellaCell. Signal. 21:220-79356464Pubmed1997Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factorHolgado-Madruga, MMoscatello, DKEmlet, DRDieterich, RWong, AJProc Natl Acad Sci U S A 94:12419-2415550174Pubmed2004The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathwayMattoon, DRLamothe, BLax, ISchlessinger, JBMC Biol 2:2411334882Pubmed2001A yeast two-hybrid study of human p97/Gab2 interactions with its SH2 domain-containing binding partnersCrouin, CArnaud, MGesbert, FCamonis, JBertoglio, JFEBS Lett. 495:148-5315170389Pubmed2004Interaction of the tyrosine phosphatase SHP-2 with Gab2 regulates Rho-dependent activation of the c-fos serum response element by interleukin-2Arnaud, MaryMzali, RymGesbert, FranckCrouin, CatherineGuenzi, ChristineVermot-Desroches, ClaudineWijdenes, JohnCourtois, GenevièveBernard, OlivierBertoglio, JacquesBiochem. J. 382:545-5625528308Pubmed2015Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesisWang, WeiyeXu, SuowenYin, MeimeiJin, Zheng GenInt. J. Cardiol. 181:180-410871282Pubmed2000Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responsesSchaeper, UGehring, N HFuchs, K PSachs, MKempkes, BBirchmeier, WJ. Cell Biol. 149:1419-3219909369Pubmed2009Phosphoinositide 3-kinase-regulated adapters in lymphocyte activationZhang, Ting-TingLi, HongzhaoCheung, Samuel MCostantini, Jennifer LHou, SenAl-Alwan, MontherMarshall, Aaron JImmunol. Rev. 232:255-72p-5Y-GAB in the RET-GRB2-GAB complexes binds p85-PI3Kp-5Y-GAB in the RET-GRB2-GAB complexes binds p85-PI3KFollowing recruitment and phosphorylation of GAB1 or GAB2 to the RET complex, it binds the p85 subunit of p85-containing PI3 kinase (p85-PI3K), resulting in its activation (Murakami et al. 1999, Hayashi et al. 2000, Besset et al. 2000). p85-PI3K consists of a p85 adaptor subunit, which contains one Src homology 3 (SH3) and two Src homology 2 (SH2) domains, and a p110 subunit that has catalytic activity (Kapeller & Cantley 1994). These subunits are tightly associated (Carpenter et al. 1990). Though p85-PI3K can be phosphorylated, it is binding of the p85 SH2 domains that activates the enzyme (Rordorf-Nikolic et al. 1995). <br><br>GAB2 has three tyrosine residues, Y452, Y476 and Y584, which are involved in p85-PI3K binding (Crouin et al. 2001, Maus et al. 2009). GAB1 also becomes tyrosine phosphorylated and directly associates with p85 when transducing signals from receptor tyrosine kinases to p85 (Holgado-Madruga et al. 1997, Mattoon et al. 2004). There are three potential binding sites for p85 on GAB1 (Y447, Y472, and Y589) (Holgado-Madruga et al. 1997). Phosphorylation at these sites in GAB1 is represented in this reaction as a likely prerequisite for p85 binding, but this is not experimentally confirmed, hence this reaction is displayed as an uncertain event.Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88553021Converted from EntitySet in ReactomeReactome DB_ID: 5082481p85-containing Class 1A PI3Ks [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 885552312x p-5Y-RET:GDNF:GFRA complexes with, without p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:p85-containing Class 1A PI3Ks [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes with, without p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:p85-containing Class 1A PI3KsReactome DB_ID: 88553021Converted from EntitySet in ReactomeReactome DB_ID: 5082481Reactome Database ID Release 758855523Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855523ReactomeR-HSA-88555232Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855523.2Reactome Database ID Release 758854905Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854905ReactomeR-HSA-88549052Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854905.28086005Pubmed1994Phosphatidylinositol 3-kinaseKapeller, RCantley, Lewis CBioessays 16:565-762174051Pubmed1990Purification and characterization of phosphoinositide 3-kinase from rat liverCarpenter, CLDuckworth, BCAuger, KRCohen, BSchaffhausen, BSCantley, Lewis CJ Biol Chem 265:19704-117876105Pubmed1995Regulation of phosphatidylinositol 3'-kinase by tyrosyl phosphoproteins. Full activation requires occupancy of both SH2 domains in the 85-kDa regulatory subunitRordorf-Nikolic, TVan Horn, D JChen, DWhite, MFBacker, J MJ. Biol. Chem. 270:3662-6p-5Y-GAB in RET-GRB2-GAB complexes binds PTPN11p-5Y-GAB in RET-GRB2-GAB complexes binds PTPN11GDNF stimulation of neuronal cells induces the assembly of a large protein complex containing RET, GRB2 and tyrosine-phosphorylated SHC1, p85 subunit of PI3K, GAB2 (GAB1 in Hayashi et al. 2000), and Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP-2) (Besset et al. 2000). <br><br>PTPN11 is recruited to RET via a combination of direct interactions and indirect interactions with other components of the receptor complex such as FRS2A and GAB1/2 (Perrinjaquet et al. 2010, Willecke et al. 2011). Binding of PTPN11 SH2-domains induces a conversion of the closed inactive into an open active structure (Willecke et al. 2011). <br><br>GAB2 interacts with the SH2 domains of PTPN11 (Gu et al. 1998, Crouin et al. 2001, Arnaud et al. 2004), which binds GAB2 Tyrosine (Y) 614 and Y643 through its N- and C-terminal SH2 domains respectively. Mutation of Y614 is sufficient to prevent GAB2 from recruiting PTPN11. In the Interleukin-2 receptor system, this prevents ERK (extracellular-signal-regulated kinase) activation (Arnaud et al. 2004). Similarly, phosphorylated GAB1 binds PTPN11, PI3K, PLCgamma1 and SHC1 in activated B cells (Ingham et al. 1998). GAB1 Y627 and Y659 appear to link it to PTPN11; GAB1 mutants that are unable to bind PTPN11 do not activate ERK (Schaeper et al. 2000, Cunnick et al. 2000, Sármay et al. 2006).Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 1625631UniProt:Q06124 PTPN11PTPN11PTP2CSHPTP2PTPN11FUNCTION Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus (PubMed:10655584, PubMed:18559669, PubMed:18829466, PubMed:26742426, PubMed:28074573). Positively regulates MAPK signal transduction pathway (PubMed:28074573). Dephosphorylates GAB1, ARHGAP35 and EGFR (PubMed:28074573). Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulation of its RhoA binding activity (PubMed:18559669). Dephosphorylates CDC73 (PubMed:26742426). Dephosphorylates SOX9 on tyrosine residues, leading to inactivate SOX9 and promote ossification (By similarity).SUBUNIT Interacts with phosphorylated LIME1 and BCAR3. Interacts with SHB and INPP5D/SHIP1 (By similarity). Interacts with MILR1 (tyrosine-phosphorylated). Interacts with FLT1 (tyrosine-phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine-phosphorylated), KIT and GRB2. Interacts with PDGFRA (tyrosine phosphorylated). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with PTPNS1 and CD84. Interacts with phosphorylated SIT1 and MPZL1. Interacts with FCRL4, FCRL6 and ANKHD1. Interacts with KIR2DL1; the interaction is enhanced by ARRB2. Interacts with GAB2. Interacts with TERT; the interaction retains TERT in the nucleus. Interacts with PECAM1 and FER. Interacts with EPHA2 (activated); participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream signaling. Interacts with ROS1; mediates PTPN11 phosphorylation. Interacts with PDGFRB (tyrosine phosphorylated); this interaction increases the PTPN11 phosphatase activity. Interacts with GAREM1 isoform 1 (tyrosine phosphorylated); the interaction increases MAPK/ERK activity and does not affect the GRB2/SOS complex formation. Interacts with CDC73 (PubMed:26742426). Interacts with CEACAM1 (via cytoplasmic domain); this interaction depends on the monomer/dimer equilibrium and is phosphorylation-dependent (By similarity). Interacts with MPIG6B (via ITIM motif) (PubMed:23112346). Interacts with SIGLEC10 (By similarity). Interacts with FCRL3 (via phosphorylated ITIM motifs) (PubMed:11162587, PubMed:19843936).TISSUE SPECIFICITY Widely expressed, with highest levels in heart, brain, and skeletal muscle.DOMAIN The SH2 domains repress phosphatase activity. Binding of these domains to phosphotyrosine-containing proteins relieves this auto-inhibition, possibly by inducing a conformational change in the enzyme.PTM Phosphorylated on Tyr-542 and Tyr-580 upon receptor protein tyrosine kinase activation; which creates a binding site for GRB2 and other SH2-containing proteins. Phosphorylated upon activation of the receptor-type kinase FLT3. Phosphorylated upon activation of the receptor-type kinase PDGFRA (By similarity). Phosphorylated by activated PDGFRB.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily.UniProtQ061241EQUAL597EQUALReactome DB_ID: 88553021Reactome DB_ID: 885576212x p-5Y-RET:GDNF:GFRA complexes with, without p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:PTPN11 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes with, without p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:PTPN11Reactome DB_ID: 16256311EQUAL597EQUALReactome DB_ID: 88553021Reactome Database ID Release 758855762Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855762ReactomeR-HSA-88557622Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855762.2Reactome Database ID Release 758855508Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855508ReactomeR-HSA-88555082Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855508.222015719Pubmed2011The tyrosine phosphatase Shp2 acts downstream of GDNF/Ret in branching morphogenesis of the developing mouse kidneyWillecke, ReginaHeuberger, JulianGrossmann, KatjaMichos, OdysséSchmidt-Ott, KaiWalentin, KatharinaCostantini, FrankBirchmeier, WalterDev. Biol. 360:310-79804835Pubmed1998The Gab1 protein is a docking site for multiple proteins involved in signaling by the B cell antigen receptorIngham, R JHolgado-Madruga, MSiu, CWong, A JGold, M RJ. Biol. Chem. 273:30630-72x p-5Y-RET:GDNF:GFRA complexes bind GRB7,102x p-5Y-RET:GDNF:GFRA complexes bind GRB7,10Tyrosine-phosphorylated RET can bind GRB7 or GRB10 via tyrosine-905 (Pandey et al. 1995, 1996).Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88541601Converted from EntitySet in ReactomeReactome DB_ID: 88547731GRB7,GRB10 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGRB7 [cytosol]GRB10 [cytosol]UniProtQ14451UniProtQ13322Reactome DB_ID: 885476812x p-5Y-RET:GDNF:GFRA complexes:GRB7,GRB10 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:GRB7,GRB10Reactome DB_ID: 88541601Converted from EntitySet in ReactomeReactome DB_ID: 88547731Reactome Database ID Release 758854768Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854768ReactomeR-HSA-88547682Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854768.2Reactome Database ID Release 758853753Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853753ReactomeR-HSA-88537532Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853753.28631863Pubmed1996Direct association between the Ret receptor tyrosine kinase and the Src homology 2-containing adapter protein Grb7Pandey, ALiu, XDixon, J EDi Fiore, P PDixit, V MJ. Biol. Chem. 271:10607-107665556Pubmed1995The Ret receptor protein tyrosine kinase associates with the SH2-containing adapter protein Grb10Pandey, ADuan, HDi Fiore, P PDixit, V MJ. Biol. Chem. 270:21461-32x p-5Y-RET:GDNF:GFRA complexes bind PLCgamma12x p-5Y-RET:GDNF:GFRA complexes bind PLCgamma1Phosphorylated RET binds Phospholipase C gamma 1 (PLCG1) via tyrosine 905 (Borello et al. 1996) and/or tyrosine-1015 (Lundgren et al. 2012).Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88541601Reactome DB_ID: 2023201UniProt:P19174 PLCG1PLCG1PLCG1PLC1FUNCTION Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, FGFR1, FGFR2, FGFR3 and FGFR4. Plays a role in actin reorganization and cell migration.ACTIVITY REGULATION Activated by phosphorylation on tyrosine residues.SUBUNIT Interacts with AGAP2 via its SH3 domain. Interacts (via SH2 domain) with RET. Interacts with FLT1 (tyrosine-phosphorylated) (By similarity). Interacts (via SH2 domain) with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with LAT (phosphorylated) upon TCR activation. Interacts (via SH3 domain) with the Pro-rich domain of TNK1. Associates with BLNK, VAV1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB in activated T-cells; which inhibits phosphorylation. Interacts with SHB. Interacts (via SH3 domain) with the Arg/Gly-rich-flanked Pro-rich domains of KHDRBS1/SAM68. This interaction is selectively regulated by arginine methylation of KHDRBS1/SAM68. Interacts with INPP5D/SHIP1, THEMIS and CLNK (By similarity). Interacts with AXL, FLT4 and KIT. Interacts with RALGPS1. Interacts (via the SH2 domains) with VIL1 (phosphorylated at C-terminus tyrosine phosphorylation sites). Interacts (via SH2 domain) with PDGFRA and PDGFRB (tyrosine phosphorylated). Interacts with PIP5K1C (By similarity). Interacts with NTRK1 and NTRK2 (phosphorylated upon ligand-binding). Interacts with SYK; activates PLCG1. Interacts with GRB2, LAT and THEMIS upon TCR activation in thymocytes (By similarity). Interacts with TESPA1; the association is increased with prolonged stimulation of the TCR and may facilitate the assembly of the LAT signalosome.SUBUNIT (Microbial infection) Interacts (via SH3 domain) with HEV ORF3 protein.DOMAIN The SH3 domain mediates interaction with CLNK (By similarity). The SH3 domain also mediates interaction with RALGPS1.PTM Tyrosine phosphorylated in response to signaling via activated FLT3, KIT and PDGFRA (By similarity). Tyrosine phosphorylated by activated FGFR1, FGFR2, FGFR3 and FGFR4. Tyrosine phosphorylated by activated FLT1 and KDR. Tyrosine phosphorylated by activated PDGFRB. The receptor-mediated activation of PLCG1 involves its phosphorylation by tyrosine kinases, in response to ligation of a variety of growth factor receptors and immune system receptors. For instance, SYK phosphorylates and activates PLCG1 in response to ligation of the B-cell receptor. May be dephosphorylated by PTPRJ. Phosphorylated by ITK and TXK on Tyr-783 upon TCR activation in T-cells.PTM Ubiquitinated by CBLB in activated T-cells.UniProtP191742EQUAL1290EQUALReactome DB_ID: 885477612x p-5Y-RET:GDNF:GFRA complexes:PLCG1 [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:PLCG1Reactome DB_ID: 88541601Reactome DB_ID: 20232012EQUAL1290EQUALReactome Database ID Release 758854776Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854776ReactomeR-HSA-88547762Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854776.2Reactome Database ID Release 758853755Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853755ReactomeR-HSA-88537552Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853755.28628282Pubmed1996The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phospholipase CgammaBorrello, M GAlberti, LArighi, EBongarzone, IBattistini, CBardelli, APasini, BPiutti, CRizzetti, M GMondellini, PRadice, M TPierotti, M AMol. Cell. Biol. 16:2151-6322355350Pubmed2012RET PLCγ phosphotyrosine binding domain regulates Ca2+ signaling and neocortical neuronal migrationLundgren, T KalleNakahata, KatsutoshiFritz, NicolasRebellato, PaolaZhang, SongbaiUhlén, PerPLoS ONE 7:e312582x p-5Y-RET:GDNF:GFRA complexes bind SRC1, RAP1GAP2x p-5Y-RET:GDNF:GFRA complexes bind SRC1, RAP1GAPRET phospho-Tyr981 binds the cytoplasmic tyrosine kinase SRC (Encinas et al. 2004). Recently, a yeast-two-hybrid screen led to the identification of the GTPase-activating protein (GAP) for Rap1, RAP1GAP, as a novel RET-binding protein (Jiao et al. 2011). Like SRC, Rap1GAP was also found to require phosphorylation of Tyrosine-981 for RET binding and suppressed GDNF-induced activation of ERK and neurite outgrowth.Authored: Jupe, Steve, 2016-01-25Reviewed: Morales, Daniel, 2016-05-06Reviewed: Luo, Wenqin, 2016-05-17Edited: Jupe, Steve, 2016-04-28Reactome DB_ID: 88541601Converted from EntitySet in ReactomeReactome DB_ID: 88557531SRC-1, RAP1GAP [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRAP1GAP [cytosol]SRC-1 [cytosol]UniProtP47736UniProtP12931-1Reactome DB_ID: 885574812x p-5Y-RET:GDNF:GFRA complexes:SRC-1,RAP1GAP [plasma membrane]2x p-5Y-RET:GDNF:GFRA complexes:SRC-1,RAP1GAPReactome DB_ID: 88541601Converted from EntitySet in ReactomeReactome DB_ID: 88557531Reactome Database ID Release 758855748Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855748ReactomeR-HSA-88557482Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855748.2Reactome Database ID Release 758855747Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8855747ReactomeR-HSA-88557472Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8855747.2Reactome Database ID Release 758853659Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8853659ReactomeR-HSA-88536594Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8853659.47906866Pubmed1994A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinomaHofstra, R MLandsvater, R MCeccherini, IStulp, R PStelwagen, TLuo, YPasini, BHöppener, J Wvan Amstel, HKRomeo, GNature 367:375-68114940Pubmed1994Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor RetSchuchardt, AD'Agati, VLarsson-Blomberg, LCostantini, FPachnis, VNature 367:380-37906417Pubmed1994Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2BCarlson, K MDou, SChi, DScavarda, NToshima, KJackson, C EWells, S AGoodfellow, P JDonis-Keller, HelenProc. Natl. Acad. Sci. U.S.A. 91:1579-832406025Pubmed1990PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomasGrieco, MSantoro, MBerlingieri, M TMelillo, R MDonghi, RBongarzone, IPierotti, M ADella Porta, GFusco, AVecchio, GCell 60:557-638114938Pubmed1994Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's diseaseRomeo, GRonchetto, PLuo, YBarone, VSeri, MCeccherini, IPasini, BBocciardi, RLerone, MKääriäinen, HNature 367:377-825838128Pubmed2015Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptorsFleming, Michael SVysochan, AnnaPaixão, SόniaNiu, JingwenKlein, RüdigerSavitt, Joseph MLuo, WenqinElife 4:e0682816237148Pubmed2006Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fateNaughton, Cathy KJain, SanjayStrickland, Amy MGupta, AkshayMilbrandt, JeffreyBiol. Reprod. 74:314-2111713247Pubmed2002Coordinated activation of autophosphorylation sites in the RET receptor tyrosine kinase: importance of tyrosine 1062 for GDNF mediated neuronal differentiation and survivalCoulpier, MurielAnders, JonasIbáñez, Carlos FJ. Biol. Chem. 277:1991-98114939Pubmed1994Mutations of the RET proto-oncogene in Hirschsprung's diseaseEdery, PLyonnet, SMulligan, L MPelet, ADow, EAbel, LHolder, SNihoul-Fékété, CPonder, B AMunnich, ANature 367:378-8011641220Pubmed2001RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neuronsEnomoto, HCrawford, P AGorodinsky, AHeuckeroth, R OJohnson, E MMilbrandt, JDevelopment 128:3963-748099202Pubmed1993Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2AMulligan, L MKwok, J BHealey, C SElsdon, M JEng, CGardner, ELove, D RMole, S EMoore, J KPapi, LNature 363:458-6016600854Pubmed2006Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor-axon pathway selection in the limbKramer, Edgar RKnott, LauraSu, FengyunDessaud, EricKrull, Catherine EHelmbacher, FrançoiseKlein, RüdigerNeuron 50:35-47