RET signaling (Homo sapiens)
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Description
The 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).
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. View original pathway at:Reactome.
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. View original pathway at:Reactome.
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DataNodes
p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:GAB1,GAB2p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:PTPN11p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:p85-containing Class 1A PI3Ksp-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1p-5Y-RET:GDNF:GFRA
complexes:DOK1,DOK2,DOK4,DOK5,DOK6p-5Y-RET:GDNF:GFRA
complexes:FRS2p-5Y-RET:GDNF:GFRA
complexes:GRB2-1:SOS1p-5Y-RET:GDNF:GFRA
complexes:GRB7,GRB10p-5Y-RET:GDNF:GFRA
complexes:PLCG1p-5Y-RET:GDNF:GFRA complexes:RET
interactorsp-5Y-RET:GDNF:GFRA
complexes:SHC1p-5Y-RET:GDNF:GFRA
complexes:SRC-1,RAP1GAPp-5Y-RET:GDNF:GFRA
complexes:p-Y349,Y350,Y427-SHC1:GRB2-1:SOS1p-5Y-RET:GDNF:GFRA
complexes:p-Y349,Y350,Y427-SHC1p-5Y-RET:GDNF:GFRA
complexesThe importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
complexes with and
without p-SHC1Annotated Interactions
p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:GAB1,GAB2p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:GAB1,GAB2p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:PTPN11p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:p85-containing Class 1A PI3Ksp-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1p-5Y-RET:GDNF:GFRA complexes with, without
p-SHC1:GRB2-1p-5Y-RET:GDNF:GFRA
complexes:DOK1,DOK2,DOK4,DOK5,DOK6p-5Y-RET:GDNF:GFRA
complexes:FRS2p-5Y-RET:GDNF:GFRA
complexes:GRB2-1:SOS1p-5Y-RET:GDNF:GFRA
complexes:GRB7,GRB10p-5Y-RET:GDNF:GFRA
complexes:PLCG1p-5Y-RET:GDNF:GFRA complexes:RET
interactorsp-5Y-RET:GDNF:GFRA
complexes:SHC1p-5Y-RET:GDNF:GFRA
complexes:SHC1p-5Y-RET:GDNF:GFRA
complexes:SRC-1,RAP1GAPp-5Y-RET:GDNF:GFRA
complexes:p-Y349,Y350,Y427-SHC1:GRB2-1:SOS1p-5Y-RET:GDNF:GFRA
complexes:p-Y349,Y350,Y427-SHC1p-5Y-RET:GDNF:GFRA
complexes:p-Y349,Y350,Y427-SHC1p-5Y-RET:GDNF:GFRA
complexesp-5Y-RET:GDNF:GFRA
complexesp-5Y-RET:GDNF:GFRA
complexesp-5Y-RET:GDNF:GFRA
complexesp-5Y-RET:GDNF:GFRA
complexesp-5Y-RET:GDNF:GFRA
complexesp-5Y-RET:GDNF:GFRA
complexesp-5Y-RET:GDNF:GFRA
complexesp-5Y-RET:GDNF:GFRA
complexesGDNF 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).
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).
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).
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).
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.
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).
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.
Rap1GAP can bind phosphorylated Y981 to suppress GDNF-induced activation of ERK and neurite outgrowth (Jiao et al. 2011).
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).
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.
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).
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.
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).
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).
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.
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.
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).
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).
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).
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).
complexes with and
without p-SHC1