MET activation by its ligand HGF induces MET kinase catalytic activity, which triggers transphosphorylation of Tyr1234 and Tyr1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively known as the invasive growth program; proliferation and survival (resistance to apoptotic signals), increased cell motility, cell dissociation (scattering), epithelial tubulogenesis, infiltration of tissues, and stimulation of angiogenesis (Appleman et al). The transducers interact with the intracellular multisubstrate docking site of MET either directly, such as GRB2, SHC, SRC, and the p85 regulatory subunit of PI3K, or indirectly through the scaffolding protein GAB1.
Phosphorylation of Tyr1349 and Tyr1356 of the multisubstrate docking site mediates interaction with GAB1, SRC, and SHC, while only Tyr 1356 is involved in the recruitment of GRB2, phospholipase C γ (PLC-γ), p85, and SHP2.
GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity. Upon interaction with MET, GAB1 becomes phosphorylated on several tyrosine residues which, in turn, recruit a number of signaling effectors, including PI3K, SHP2, and PLC-γ. GAB1 phosphorylation by MET results in a sustained signal that mediates most of the downstream signaling pathways. (Description adapted from [https://en.wikipedia.org/wiki/C-Met Wikipedia]).
MET is a proto-oncogene, meaning that regulated expression of the wild-type allele plays a role in normal physiologic processes, and malignant transformation occurs when MET activity is increased in- appropriately and/or constitutively activated (Appleman et al). Phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.
abd
e43
cda
c44
ad2
bbb
f75
parentid=P08581; parentsymbol=MET; site=yVHVNAtyVNVKCVA; position=tyr1356; sitegrpid=448473; ptm=p; direction=u
parentid=P08581; parentsymbol=MET; site=RDMyDkEyysVHNkt; position=tyr1234; sitegrpid=448470; ptm=p; direction=u
parentid=P08581; parentsymbol=MET; site=DMyDkEyysVHNktG; position=tyr1235; sitegrpid=448471; ptm=p; direction=u
parentid=P08581; parentsymbol=MET; site=stFIGEHyVHVNAty; position=tyr1349; sitegrpid=448472; ptm=p; direction=u
parentid=P04049; parentsymbol=RAF1; site=IGDFGLAtVksRWsG; position=thr491; sitegrpid=447748; ptm=p; direction=u
parentid=Q02750; parentsymbol=MAP2K1; site=VsGQLIDsMANsFVG; position=ser218; sitegrpid=448514; ptm=p; direction=u
parentid=Q02750; parentsymbol=MAP2K1; site=LIDsMANsFVGTRSY; position=ser222; sitegrpid=448513; ptm=p; direction=u
parentid=P36507; parentsymbol=MAP2K2; site=VsGQLIDsMANsFVG; position=ser222; sitegrpid=448073; ptm=p; direction=u
parentid=P36507; parentsymbol=MAP2K2; site=LIDsMANsFVGTRSY; position=ser226; sitegrpid=448074; ptm=p; direction=u
parentid=P28482; parentsymbol=MAPK1; site=HtGFLtEyVAtRWyR; position=tyr187; sitegrpid=447594; ptm=p; direction=u
parentid=P28482; parentsymbol=MAPK1; site=HDHtGFLtEyVAtRW; position=thr185; sitegrpid=447593; ptm=p; direction=u
parentid=P27361; parentsymbol=MAPK3; site=HtGFLtEyVAtRWyR; position=tyr204; sitegrpid=447543; ptm=p; direction=u
parentid=P27361; parentsymbol=MAPK3; site=HDHtGFLtEyVAtRW; position=thr202; sitegrpid=447542; ptm=p; direction=u
parentid=Q92934; parentsymbol=BAD; site=PFrGrsRsAPPNLWA; position=ser99; sitegrpid=447862; ptm=p; direction=d
parentid=P14921; parentsymbol=ETS1; site=CADVPLLtPSSkEMM; position=thr38; sitegrpid=447950; ptm=p; direction=d
parentid=P05412; parentsymbol=JUN; site=kNsDLLtsPDVGLLk; position=ser63; sitegrpid=447686; ptm=p; direction=d
parentid=P05412; parentsymbol=JUN; site=VGLLkLAsPELERLI; position=ser73; sitegrpid=447943; ptm=p; direction=d
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