RET signaling (Homo sapiens)

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5, 4715, 2546252, 21, 35418, 2517, 3524, 3325, 3811, 512221258, 25, 292526, 27362, 21, 352514, 506, 7, 13, 19, 23...32, 38, 421941cytosolGFRA4 GFRA3 GFRA2 2xp-5Y-RET:GDNF:GFRAcomplexes:RETinteractorsGFRA2 GFRA4 p-Y349,Y350,Y427-SHC1 PRKCA GFRA2 RETRET:GFRA:GDNFcomplexesGFRA3 GAB1 GFRA4 PIK3CB GRB2-1:SOS12xp-5Y-RET:GDNF:GFRAcomplexeswith,withoutp-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:p85-containing Class 1A PI3Ksp-5Y-RET DOK5 ARTN GFRA3 ARTN 2xp-5Y-RET:GDNF:GFRAcomplexes:p-Y349,Y350,Y427-SHC1GFRA3 ARTN PIK3CD GFRA1 PSPN GFRA4 SRC-1 GFRA1 SRC-1 GFRA4 RET IRS2 NRTN PDLIM7 DOK2 SHANK3 RET PIK3R2 GFRA4 GRB2-1 PSPN p-Y349,Y350,Y427-SHC1 ARTN NRTN PIK3CA p-5Y-RET NRTN GFRA2 PTPN11 p-Y349,Y350,Y427-SHC1 ARTN GFRA3 GDNF PIK3R3 p-5Y-RET GDNF GDNF 2x RET:GFRA:GDNFcomplexes2xp-5Y-RET:GDNF:GFRAcomplexes:SRC-1,RAP1GAPSHC3 GFRA2 GDNF FRS22xp-5Y-RET:GDNF:GFRAcomplexeswith,withoutp-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2GFRA3 GFRA4 GFRA1 GAB1 GFRA2 PSPN 2xp-5Y-RET:GDNF:GFRAcomplexes:GRB7,GRB10PSPNDOK5 ARTN ARTN RET GFRA1 RET:GFRA4SHC1ADPGDNF PRKCA GFRA1 p-5Y-GAB2 GDNF RAP1GAP GDNF PSPN PSPN ARTN NRTN GFRA4 p-5Y-RET NRTN GFRA2 SHC3 RAF/MAP kinasecascadeGFRA1 2xp-5Y-RET:GDNF:GFRAcomplexes:DOK1,DOK2,DOK4,DOK5,DOK6GFRA1 GFRA3 PSPN RET:GFRA4:PSPNp-5Y-RET ARTN PSPN NRTN RET p-5Y-RET GFRA4 PSPN GFRA3 PIK3R1 NRTN 2xp-5Y-RET:GDNF:GFRAcomplexesGFRA3 p-5Y-RET PRKACB GDNF ARTN p-5Y-RET RET:GFRA1,GFRA2ATPGFRA1 ADPGFRA4 RET GFRA1 GFRA1,GFRA3GDNF PSPN GRB2-1 Protein kinase Acatalytic subunitNRTN 2xp-5Y-RET:GDNF:GFRAcomplexes with,withoutp-SHC1:GRB2-1GFRA3 GFRA3 SOS1 p-Y349,Y350,Y427-SHC1 PSPN p-5Y-GAB1 GFRA1 RET interactorsGFRA1 GRB7,GRB10GFRA1 ARTN GFRA2 RET NRTN 2xp-5Y-RET:GDNF:GFRAcomplexes:p-Y349,Y350,Y427-SHC1:GRB2-1:SOS1NRTN PTPN11PSPN PSPN PLCG1PSPN p-5Y-RET NRTN PSPN GFRA4 GFRA4 SOS1 GDNF NRTN p-5Y-RET GFRA3 GFRA1 GFRA1 GFRA2 GRB2-1 MAPK7 2xp-5Y-RET:GDNF:GFRAcomplexes:PLCG1p-5Y-GAB1 RET SOS1 IRS2 GFRA3 ARTN GFRA1, GFRA2ARTN ATPGFRA2 GFRA1 ARTN GRB2-1 GDNF GFRA2 PSPN GAB1,GAB2GFRA4 ARTN GFRA2 NRTN DOK4 NRTN PRKACA GFRA4 NRTN PSPN ARTN GFRA2 2xp-S696-RET:GFRA:GDNF complexesPIK3CD PSPN p-5Y-GAB2 GFRA1 PRKACG GFRA1 RET:GFRA1,GFRA2:GDNF,NRTNGDNF p-5Y-RET p-5Y-RET GFRA1 DOK1 DOK4 p-5Y-GAB2 ATPGFRA3 FRS2 GDNF PIK3R2 GRB7 NRTN GDNF GDNF GFRA4 GFRA2 GFRA3 GFRA4 GAB2 GRB2-1 p-Y349,Y350,Y427-SHC1 PSPN p-Y349,Y350,Y427-SHC1 GRB10 GDNF,NRTNGFRA3 PLCG1 GFRA3 GFRA3 GFRA4 GFRA2 ARTN ADPGFRA2 p-Y349,Y350,Y427-SHC1 PSPN MAPK7 GFRA3 GAB2 NRTN PSPN PSPN p-5Y-RET NRTN RET ARTN2xp-5Y-RET:GDNF:GFRAcomplexes:SHC12xp-5Y-RET:GDNF:GFRAcomplexes:FRS2GRB2-1GRB2-1 GFRA1 2xp-5Y-RET:GDNF:GFRAcomplexeswith,withoutp-SHC1:GRB2-1:GAB1,GAB2PDLIM7 p-5Y-GAB1 2xp-5Y-RET:GDNF:GFRAcomplexeswith,withoutp-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:PTPN11GFRA2 GRB2-1 ARTN ARTN GFRA4p-Y349,Y350,Y427-SHC1 p-5Y-RET GFRA2 GFRA4 NRTN GFRA3 GFRA2 GFRA4 GDNF DOK1 p-5Y-RET GDNF GFRA1 p-5Y-RET PIK3R1 RET:GFRA1,GFRA3:ARTNGDNF GDNF GFRA4 GFRA4 GFRA4 GFRA1 GFRA2 GFRA3 ARTN GFRA1 GFRA1 ARTN RET GFRA1 GFRA2 SHC1 GRB7 SHANK3 GFRA2 SRC-1, RAP1GAPNRTN PIK3CB GRB10 RET:GFRA1,GFRA3GDNF PIK3R3 RAP1GAP GFRA2 2xp-5Y-RET:GDNF:GFRAcomplexes:GRB2-1:SOS1DOK1,DOK2,DOK4,DOK5,DOK6GDNF p-5Y-RET:GDNF:GFRAcomplexes with andwithout p-SHC1GFRA3 DOK2 PIK3CA GRB2-1 NRTN GDNF p-5Y-RET NRTN DOK6 p85-containing Class1A PI3KsGFRA3 DOK6 GFRA1 GFRA1 319, 123, 4, 10, 16, 18...9, 121, 4431


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.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8853659
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Jupe, Steve

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101434view11:31, 1 November 2018ReactomeTeamreactome version 66
100973view21:08, 31 October 2018ReactomeTeamreactome version 65
100510view19:42, 31 October 2018ReactomeTeamreactome version 64
100056view16:26, 31 October 2018ReactomeTeamreactome version 63
99608view14:59, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99220view12:44, 31 October 2018ReactomeTeamreactome version 62
93511view11:25, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:GAB1,GAB2
ComplexR-HSA-8855090 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:PTPN11
ComplexR-HSA-8855762 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:p85-containing Class 1A PI3Ks
ComplexR-HSA-8855523 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2
ComplexR-HSA-8855302 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1
ComplexR-HSA-8854907 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:DOK1,DOK2,DOK4,DOK5,DOK6
ComplexR-HSA-8855573 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:FRS2
ComplexR-HSA-8855579 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:GRB2-1:SOS1
ComplexR-HSA-8854903 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:GRB7,GRB10
ComplexR-HSA-8854768 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:PLCG1
ComplexR-HSA-8854776 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes:RET

interactors
ComplexR-HSA-8855914 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:SHC1
ComplexR-HSA-8854400 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:SRC-1,RAP1GAP
ComplexR-HSA-8855748 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:p-Y349,Y350,Y427-SHC1:GRB2-1:SOS1
ComplexR-HSA-8854399 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:p-Y349,Y350,Y427-SHC1
ComplexR-HSA-8854980 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
ComplexR-HSA-8854160 (Reactome)
2x p-S696-RET:GFRA:GDNF complexesComplexR-HSA-8855760 (Reactome)
2x RET:GFRA:GDNF complexesComplexR-HSA-8853818 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ARTN ProteinQ5T4W7 (Uniprot-TrEMBL)
ARTNProteinQ5T4W7 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
DOK1 ProteinQ99704 (Uniprot-TrEMBL)
DOK1,DOK2,DOK4,DOK5,DOK6ComplexR-HSA-8855619 (Reactome)
DOK2 ProteinO60496 (Uniprot-TrEMBL)
DOK4 ProteinQ8TEW6 (Uniprot-TrEMBL)
DOK5 ProteinQ9P104 (Uniprot-TrEMBL)
DOK6 ProteinQ6PKX4 (Uniprot-TrEMBL)
FRS2 ProteinQ8WU20 (Uniprot-TrEMBL)
FRS2ProteinQ8WU20 (Uniprot-TrEMBL)
GAB1 ProteinQ13480 (Uniprot-TrEMBL)
GAB1,GAB2ComplexR-HSA-8855092 (Reactome)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GDNF ProteinP39905 (Uniprot-TrEMBL)
GDNF,NRTNComplexR-HSA-8853802 (Reactome)
GFRA1 ProteinP56159 (Uniprot-TrEMBL)
GFRA1, GFRA2ComplexR-HSA-8853803 (Reactome)
GFRA1,GFRA3ComplexR-HSA-8853799 (Reactome)
GFRA2 ProteinO00451 (Uniprot-TrEMBL)
GFRA3 ProteinO60609 (Uniprot-TrEMBL)
GFRA4 ProteinQ9GZZ7 (Uniprot-TrEMBL)
GFRA4ProteinQ9GZZ7 (Uniprot-TrEMBL)
GRB10 ProteinQ13322 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB7 ProteinQ14451 (Uniprot-TrEMBL)
GRB7,GRB10ComplexR-HSA-8854773 (Reactome)
IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
MAPK7 ProteinQ13164 (Uniprot-TrEMBL)
NRTN ProteinQ99748 (Uniprot-TrEMBL)
PDLIM7 ProteinQ9NR12 (Uniprot-TrEMBL)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PSPN ProteinO60542 (Uniprot-TrEMBL)
PSPNProteinO60542 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
Protein kinase A catalytic subunitComplexR-HSA-425833 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The 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).
RAP1GAP ProteinP47736 (Uniprot-TrEMBL)
RET ProteinP07949 (Uniprot-TrEMBL)
RET interactorsComplexR-HSA-8855913 (Reactome)
RET:GFRA1,GFRA2:GDNF,NRTNComplexR-HSA-8853805 (Reactome)
RET:GFRA1,GFRA2ComplexR-HSA-8855759 (Reactome)
RET:GFRA1,GFRA3:ARTNComplexR-HSA-8853795 (Reactome)
RET:GFRA1,GFRA3ComplexR-HSA-8855745 (Reactome)
RET:GFRA4:PSPNComplexR-HSA-8853798 (Reactome)
RET:GFRA4ComplexR-HSA-8855751 (Reactome)
RET:GFRA:GDNF complexesComplexR-HSA-8853817 (Reactome)
RETProteinP07949 (Uniprot-TrEMBL)
SHANK3 ProteinQ9BYB0 (Uniprot-TrEMBL)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SHC3 ProteinQ92529 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
SRC-1, RAP1GAPComplexR-HSA-8855753 (Reactome)
p-5Y-GAB1 ProteinQ13480 (Uniprot-TrEMBL)
p-5Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p-5Y-RET ProteinP07949 (Uniprot-TrEMBL)
p-5Y-RET:GDNF:GFRA

complexes with and

without p-SHC1
ComplexR-HSA-8854900 (Reactome)
p-Y349,Y350,Y427-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p85-containing Class 1A PI3KsComplexR-HSA-508248 (Reactome) This set represents Class 1A PI3Ks including all three genes that can give rise to the five isoforms of the regulatory subunit. Note that the p85 alpha form is almost always the form used as a reagent experimentally and measured by p85-Abs.The other forms are rarely used or determined experimentally. Also note that Class 1A PI3Ks may not be the most relevant physiologically in some cell types (e.g. T cells). There are five variants of the p85 regulatory subunit, designated p85alpha, p55alpha, p50alpha, p85beta, and p55gamma. There are also three variants of the p110 catalytic subunit designated p110alpha, beta, or gamma catalytic subunit. The first three regulatory subunits are all splice variants of the same gene (Pik3r1), the other two are expressed by Pik3r2 and Pik3r3, respectively). The most highly expressed regulatory subunit is p85alpha. All three catalytic subunits are expressed by separate genes (Pik3ca, Pik3cb, and Pik3cd for p110alpha, p110beta and p110gamma, respectively). The alpha and beta p110s are expressed in all cells, while p110gamma is expressed primarily in leukocytes. It has been suggested that it evolved in parallel with the adaptive immune system. The regulatory p101 and catalytic p110gamma subunits comprise the class IB PI3Ks, each is encoded by a single gene.

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:GAB1,GAB2
ArrowR-HSA-8854897 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:GAB1,GAB2
R-HSA-8853774 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:PTPN11
ArrowR-HSA-8855508 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2:p85-containing Class 1A PI3Ks
ArrowR-HSA-8854905 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2
ArrowR-HSA-8853774 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2
R-HSA-8854905 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1:p-5Y-GAB1,p-5Y-GAB2
R-HSA-8855508 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1
ArrowR-HSA-8853793 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes with, without

p-SHC1:GRB2-1
R-HSA-8854897 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:DOK1,DOK2,DOK4,DOK5,DOK6
ArrowR-HSA-8855617 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:FRS2
ArrowR-HSA-8855564 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:GRB2-1:SOS1
ArrowR-HSA-8854899 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:GRB7,GRB10
ArrowR-HSA-8853753 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:PLCG1
ArrowR-HSA-8853755 (Reactome)
2x

p-5Y-RET:GDNF:GFRA complexes:RET

interactors
ArrowR-HSA-8855915 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:SHC1
ArrowR-HSA-8853737 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:SHC1
R-HSA-8854981 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:SRC-1,RAP1GAP
ArrowR-HSA-8855747 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:p-Y349,Y350,Y427-SHC1:GRB2-1:SOS1
ArrowR-HSA-8853734 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:p-Y349,Y350,Y427-SHC1
ArrowR-HSA-8854981 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes:p-Y349,Y350,Y427-SHC1
R-HSA-8853734 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
ArrowR-HSA-8853792 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
R-HSA-8853737 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
R-HSA-8853753 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
R-HSA-8853755 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
R-HSA-8854899 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
R-HSA-8855564 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
R-HSA-8855617 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
R-HSA-8855747 (Reactome)
2x

p-5Y-RET:GDNF:GFRA

complexes
R-HSA-8855915 (Reactome)
2x p-S696-RET:GFRA:GDNF complexesArrowR-HSA-8854908 (Reactome)
2x RET:GFRA:GDNF complexesArrowR-HSA-8853762 (Reactome)
2x RET:GFRA:GDNF complexesR-HSA-8853792 (Reactome)
2x RET:GFRA:GDNF complexesR-HSA-8854908 (Reactome)
2x RET:GFRA:GDNF complexesmim-catalysisR-HSA-8853792 (Reactome)
ADPArrowR-HSA-8853774 (Reactome)
ADPArrowR-HSA-8853792 (Reactome)
ADPArrowR-HSA-8854908 (Reactome)
ARTNR-HSA-8853800 (Reactome)
ATPR-HSA-8853774 (Reactome)
ATPR-HSA-8853792 (Reactome)
ATPR-HSA-8854908 (Reactome)
DOK1,DOK2,DOK4,DOK5,DOK6R-HSA-8855617 (Reactome)
FRS2R-HSA-8855564 (Reactome)
GAB1,GAB2R-HSA-8854897 (Reactome)
GDNF,NRTNR-HSA-8853789 (Reactome)
GFRA1, GFRA2R-HSA-8871226 (Reactome)
GFRA1,GFRA3R-HSA-8853745 (Reactome)
GFRA4R-HSA-8871227 (Reactome)
GRB2-1:SOS1R-HSA-8853734 (Reactome)
GRB2-1:SOS1R-HSA-8854899 (Reactome)
GRB2-1R-HSA-8853793 (Reactome)
GRB7,GRB10R-HSA-8853753 (Reactome)
PLCG1R-HSA-8853755 (Reactome)
PSPNR-HSA-8853801 (Reactome)
PTPN11R-HSA-8855508 (Reactome)
Protein kinase A catalytic subunitmim-catalysisR-HSA-8854908 (Reactome)
R-HSA-8853734 (Reactome) RET 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).

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).

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).
R-HSA-8853737 (Reactome) 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). RET binds SHC1 via phosphorylated tyrosine-1062 (Asai et al. 1996, Arighi et al. 1997).
R-HSA-8853745 (Reactome) RET 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).
R-HSA-8853753 (Reactome) Tyrosine-phosphorylated RET can bind GRB7 or GRB10 via tyrosine-905 (Pandey et al. 1995, 1996).
R-HSA-8853755 (Reactome) Phosphorylated RET binds Phospholipase C gamma 1 (PLCG1) via tyrosine 905 (Borello et al. 1996) and/or tyrosine-1015 (Lundgren et al. 2012).
R-HSA-8853762 (Reactome) It 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).
R-HSA-8853774 (Reactome) Grb2-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).

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.
R-HSA-8853789 (Reactome) Glial 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.
R-HSA-8853792 (Reactome) RET 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).

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.
R-HSA-8853793 (Reactome) 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). 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).
R-HSA-8853800 (Reactome) Artemin (ARTN) is a ligand for GDNF family receptor-alpha (GFRA) 1 and 3, preferentially binding GFRA3 (Baloh et al. 1998).
R-HSA-8853801 (Reactome) Persephin (PSPN) is a ligand for GDNF family receptor-alpha (GFRA) 4 (Milbrandt et al. 1998, Masure et al. 2000).
R-HSA-8854897 (Reactome) Grb-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.

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.
R-HSA-8854899 (Reactome) RET 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).

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).
R-HSA-8854905 (Reactome) Following 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).

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.
R-HSA-8854908 (Reactome) Serine (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.
R-HSA-8854981 (Reactome) 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). 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).

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.
R-HSA-8855508 (Reactome) 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).

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).
R-HSA-8855564 (Reactome) RET 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).
R-HSA-8855617 (Reactome) Docking 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).

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).
R-HSA-8855747 (Reactome) RET 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.
R-HSA-8855915 (Reactome) Other 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.
R-HSA-8871226 (Reactome) RET 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).
R-HSA-8871227 (Reactome) RET 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).
RET interactorsR-HSA-8855915 (Reactome)
RET:GFRA1,GFRA2:GDNF,NRTNArrowR-HSA-8853789 (Reactome)
RET:GFRA1,GFRA2ArrowR-HSA-8871226 (Reactome)
RET:GFRA1,GFRA2R-HSA-8853789 (Reactome)
RET:GFRA1,GFRA3:ARTNArrowR-HSA-8853800 (Reactome)
RET:GFRA1,GFRA3ArrowR-HSA-8853745 (Reactome)
RET:GFRA1,GFRA3R-HSA-8853800 (Reactome)
RET:GFRA4:PSPNArrowR-HSA-8853801 (Reactome)
RET:GFRA4ArrowR-HSA-8871227 (Reactome)
RET:GFRA4R-HSA-8853801 (Reactome)
RET:GFRA:GDNF complexesR-HSA-8853762 (Reactome)
RETR-HSA-8853745 (Reactome)
RETR-HSA-8871226 (Reactome)
RETR-HSA-8871227 (Reactome)
SHC1R-HSA-8853737 (Reactome)
SRC-1, RAP1GAPR-HSA-8855747 (Reactome)
p-5Y-RET:GDNF:GFRA

complexes with and

without p-SHC1
R-HSA-8853793 (Reactome)
p85-containing Class 1A PI3KsR-HSA-8854905 (Reactome)
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