MET in type 1 papillary renal cell carcinoma (WP4205)

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).
last edited

Authors

Kristina Hanspers , Daniela Digles , Egon Willighagen , Martina Summer-Kutmon , Finterly Hu , and Eric Weitz

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organism

Homo sapiens

Communities

CPTAC Diseases Renal Genomics Pathways

Annotations

Disease Ontology: papillary renal cell carcinoma cancer

Cell Type Ontology: endothelial cell epithelial cell

Participants

Label Type Compact Identifier
foretinib Metabolite wikidata:Q5469311
PIP3 Metabolite chebi:16618
tivantinib Metabolite wikidata:Q17123902
DAG Metabolite chebi:18035
IP3 Metabolite chebi:84244
Ca2+ Metabolite chebi:29108
HGF GeneProduct ensembl:ENSG00000019991
PIK3CA GeneProduct ensembl:ENSG00000121879
STAT3 GeneProduct ensembl:ENSG00000168610
MAPK8 GeneProduct ensembl:ENSG00000107643
CBL GeneProduct ensembl:ENSG00000110395
PLCG1 GeneProduct ensembl:ENSG00000124181
MET GeneProduct ncbigene:4233
GAB1 GeneProduct ensembl:ENSG00000109458
GRB2 GeneProduct ensembl:ENSG00000177885
SOS1 GeneProduct ensembl:ENSG00000115904
SOS2 GeneProduct ensembl:ENSG00000100485
HRAS GeneProduct ensembl:ENSG00000174775
KRAS GeneProduct ensembl:ENSG00000133703
NRAS GeneProduct ensembl:ENSG00000213281
CRK GeneProduct ensembl:ENSG00000167193
CRKL GeneProduct ensembl:ENSG00000099942
RAPGEF1 GeneProduct ensembl:ENSG00000107263
PTPN11 GeneProduct ensembl:ENSG00000179295
RAP1A GeneProduct ensembl:ENSG00000116473
RAP1B GeneProduct ensembl:ENSG00000127314
ARAF GeneProduct ensembl:ENSG00000078061
RAF1 GeneProduct ensembl:ENSG00000132155
BRAF GeneProduct ensembl:ENSG00000157764
RAC1 GeneProduct ensembl:ENSG00000136238
CDC42 GeneProduct ensembl:ENSG00000070831
PAK4 GeneProduct ensembl:ENSG00000130669
BUB1B-PAK6 GeneProduct ensembl:ENSG00000259288
PAK1 GeneProduct ensembl:ENSG00000149269
PAK2 GeneProduct ensembl:ENSG00000180370
PAK3 GeneProduct ensembl:ENSG00000077264
PAK6 GeneProduct ensembl:ENSG00000137843
PAK5 GeneProduct ensembl:ENSG00000101349
MAP2K1 GeneProduct ensembl:ENSG00000169032
MAP2K2 GeneProduct ensembl:ENSG00000126934
MAPK1 GeneProduct ensembl:ENSG00000100030
MAPK3 GeneProduct ensembl:ENSG00000102882
PIK3CB GeneProduct ensembl:ENSG00000051382
PIK3CD GeneProduct ensembl:ENSG00000171608
PIK3R1 GeneProduct ensembl:ENSG00000145675
PIK3R2 GeneProduct ensembl:ENSG00000105647
PIK3R3 GeneProduct ensembl:ENSG00000117461
PIK3R3 GeneProduct ensembl:ENSG00000117461
AKT1 GeneProduct ensembl:ENSG00000142208
AKT2 GeneProduct ensembl:ENSG00000105221
AKT3 GeneProduct ensembl:ENSG00000117020
BAD GeneProduct ensembl:ENSG00000002330
ETS1 GeneProduct ensembl:ENSG00000134954
JUN GeneProduct ensembl:ENSG00000177606
ALK GeneProduct ensembl:ENSG00000171094
STRN GeneProduct ensembl:ENSG00000115808
INSL3 GeneProduct ensembl:ENSG00000248099
JAK3 GeneProduct ensembl:ENSG00000105639
TCEB3 GeneProduct ensembl:ENSG00000011007
RPL11 GeneProduct ensembl:ENSG00000142676
C8orf34 GeneProduct ensembl:ENSG00000165084
CRK GeneProduct ensembl:ENSG00000167193
PTK2 GeneProduct ensembl:ENSG00000169398
SRC GeneProduct ensembl:ENSG00000197122
MET GeneProduct ncbigene:4233
TFE3 GeneProduct ensembl:ENSG00000068323
PRCC GeneProduct ensembl:ENSG00000143294
CDKN1A GeneProduct ensembl:ENSG00000124762

References

  1. Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene. 2000 Nov 20;19(49):5582–9. PubMed Europe PMC Scholia
  2. Giubellino A, Linehan WM, Bottaro DP. Targeting the Met signaling pathway in renal cancer. Expert Rev Anticancer Ther. 2009 Jun;9(6):785–93. PubMed Europe PMC Scholia
  3. Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer. 2010 May;46(7):1260–70. PubMed Europe PMC Scholia
  4. Appleman LJ. MET signaling pathway: a rational target for cancer therapy. J Clin Oncol. 2011 Dec 20;29(36):4837–8. PubMed Europe PMC Scholia
  5. Organ SL, Tsao M-S. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011 Nov;3(1 Suppl):S7–19. PubMed Europe PMC Scholia
  6. Fay AP, Signoretti S, Choueiri TK. MET as a target in papillary renal cell carcinoma. Clin Cancer Res. 2014 Jul 1;20(13):3361–3. PubMed Europe PMC Scholia
  7. Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, et al. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med. 2016 Jan 14;374(2):135–45. PubMed Europe PMC Scholia