MET in type 1 papillary renal cell carcinoma (Homo sapiens)

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1, 2, 5-8555556Epithelial cell of proximal renal tubuleEndothelial cellNucleusCell junctionGene fusionsInvasionSurvivalMigrationCell polarityActin cytoskeletonMotilityNegative MetregulationforetinibCBLPKCVEGFRVEGFPIK3CAHGFPTPsPIP3PLCG1MAPK8STAT3METPP4PPGAB1GRB2SOS1SOS2HRASKRASNRASCRKCRKLRAPGEF1PTPN11RAP1ARAP1BARAFRAF1BRAFPRAC1CDC42PAK4BUB1B-PAK6PAK1PAK2PAK3PAK6PAK5MAP2K1PPMAP2K2PPMAPK1PMAPK3PPPPIK3CBPIK3CDPIK3R1PIK3R2PIK3R3PIK3R3AKT1AKT2AKT3BADETS1PPJUNPPCell cycle progressionProliferationALKSTRNINSL3JAK3TCEB3RPL11C8orf343tivantinibCRKTransformationPTK2SRCDAGIP3Ca2+METTFE3PRCCCDKN1ALegendActivating mutationInactivating mutation


Description

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 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.

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Bibliography

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  1. Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Vocke CD, Peto M, Al Mamun AA, Shinbrot E, Sethi A, Brooks S, Rathmell WK, Brooks AN, Hoadley KA, Robertson AG, Brooks D, Bowlby R, Sadeghi S, Shen H, Weisenberger DJ, Bootwalla M, Baylin SB, Laird PW, Cherniack AD, Saksena G, Haake S, Li J, Liang H, Lu Y, Mills GB, Akbani R, Leiserson MD, Raphael BJ, Anur P, Bottaro D, Albiges L, Barnabas N, Choueiri TK, Czerniak B, Godwin AK, Hakimi AA, Ho TH, Hsieh J, Ittmann M, Kim WY, Krishnan B, Merino MJ, Mills Shaw KR, Reuter VE, Reznik E, Shelley CS, Shuch B, Signoretti S, Srinivasan R, Tamboli P, Thomas G, Tickoo S, Burnett K, Crain D, Gardner J, Lau K, Mallery D, Morris S, Paulauskis JD, Penny RJ, Shelton C, Shelton WT, Sherman M, Thompson E, Yena P, Avedon MT, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Santos T, Wise L, Zmuda E, Demchok JA, Felau I, Hutter CM, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang J, Ayala B, Baboud J, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Ally A, Balasundaram M, Balu S, Beroukhim R, Bodenheimer T, Buhay C, Butterfield YS, Carlsen R, Carter SL, Chao H, Chuah E, Clarke A, Covington KR, Dahdouli M, Dewal N, Dhalla N, Doddapaneni HV, Drummond JA, Gabriel SB, Gibbs RA, Guin R, Hale W, Hawes A, Hayes DN, Holt RA, Hoyle AP, Jefferys SR, Jones SJ, Jones CD, Kalra D, Kovar C, Lewis L, Ma Y, Marra MA, Mayo M, Meng S, Meyerson M, Mieczkowski PA, Moore RA, Morton D, Mose LE, Mungall AJ, Muzny D, Parker JS, Perou CM, Roach J, Schein JE, Schumacher SE, Shi Y, Simons JV, Sipahimalani P, Skelly T, Soloway MG, Sougnez C, Tam A, Tan D, Thiessen N, Veluvolu U, Wang M, Wilkerson MD, Wong T, Wu J, Xi L, Zhou J, Bedford J, Chen F, Fu Y, Gerstein M, Haussler D, Kasaian K, Lai P, Ling S, Radenbaugh A, Van Den Berg D, Weinstein JN, Zhu J, Albert M, Alexopoulou I, Andersen JJ, Auman JT, Bartlett J, Bastacky S, Bergsten J, Blute ML, Boice L, Bollag RJ, Boyd J, Castle E, Chen YB, Cheville JC, Curley E, Davies B, DeVolk A, Dhir R, Dike L, Eckman J, Engel J, Harr J, Hrebinko R, Huang M, Huelsenbeck-Dill L, Iacocca M, Jacobs B, Lobis M, Maranchie JK, McMeekin S, Myers J, Nelson J, Parfitt J, Parwani A, Petrelli N, Rabeno B, Roy S, Salner AL, Slaton J, Stanton M, Thompson RH, Thorne L, Tucker K, Weinberger PM, Winemiller C, Zach LA, Zuna R; ''Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.''; N Engl J Med, 2016 PubMed Europe PMC Scholia
  2. Giubellino A, Linehan WM, Bottaro DP; ''Targeting the Met signaling pathway in renal cancer.''; Expert Rev Anticancer Ther, 2009 PubMed Europe PMC Scholia
  3. Fay AP, Signoretti S, Choueiri TK; ''MET as a target in papillary renal cell carcinoma.''; Clin Cancer Res, 2014 PubMed Europe PMC Scholia
  4. Furge KA, Zhang YW, Vande Woude GF; ''Met receptor tyrosine kinase: enhanced signaling through adapter proteins.''; Oncogene, 2000 PubMed Europe PMC Scholia
  5. Organ SL, Tsao MS; ''An overview of the c-MET signaling pathway.''; Ther Adv Med Oncol, 2011 PubMed Europe PMC Scholia
  6. Appleman LJ; ''MET signaling pathway: a rational target for cancer therapy.''; J Clin Oncol, 2011 PubMed Europe PMC Scholia
  7. Cecchi F, Rabe DC, Bottaro DP; ''Targeting the HGF/Met signalling pathway in cancer.''; Eur J Cancer, 2010 PubMed Europe PMC Scholia
  8. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E; ''PhosphoSitePlus, 2014: mutations, PTMs and recalibrations.''; Nucleic Acids Res, 2015 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
129356view09:32, 27 March 2024MkutmonOntology Term : 'cancer pathway' added !
129355view09:32, 27 March 2024MkutmonOntology Term : 'disease pathway' added !
127242view00:24, 26 August 2023Khanspersadded lit ref and updated description
118937view22:26, 4 June 2021EweitzOntology Term : 'epithelial cell' added !
118936view22:26, 4 June 2021EweitzOntology Term : 'endothelial cell' added !
118928view16:33, 4 June 2021Finterlyspelling siregrpid corrected to sitegrpid in state comments
118432view14:35, 27 May 2021Mkutmonfixed publication references
112059view21:58, 17 September 2020KhanspersModified description
112057view21:53, 17 September 2020Khanspersupdated and added ptms
112056view21:08, 17 September 2020KhanspersModified description
112055view20:54, 17 September 2020KhanspersOntology Term : 'cancer' added !
112054view20:53, 17 September 2020KhanspersOntology Term : 'papillary renal cell carcinoma' added !
105480view05:37, 8 August 2019KhanspersModified description
105443view04:54, 8 August 2019KhanspersModified description
97130view19:00, 30 April 2018Khanspersupdated lit refs, updated connections
96851view19:39, 13 April 2018Khansperscorrected placement of states
96632view22:47, 23 March 2018Khanspersupdated Chebi ids
96629view19:28, 23 March 2018Khanspersupdating gene fusions
96628view18:11, 23 March 2018KhanspersModified description
96627view18:10, 23 March 2018Khanspersupdated phosphosites and mutations
96452view09:31, 15 March 2018EgonwReplaced secondary ChEBI identifiers with primary identifiers.
96109view00:16, 17 February 2018KhanspersModified title
96011view11:14, 15 February 2018DdiglesOntology Term : 'malignant cell' added !
95923view18:14, 5 February 2018Khanspersfixed unconnected
95850view22:02, 25 January 2018Khanspersadded Appleman ref
95849view22:00, 25 January 2018KhanspersModified title
95848view21:59, 25 January 2018KhanspersOntology Term : 'altered scatter factor/hepatocyte growth factor signaling pathway' added !
95847view21:58, 25 January 2018KhanspersOntology Term : 'papillary renal cell carcinoma' added !
95845view21:55, 25 January 2018Khanspersfixed unconnected
95824view21:51, 23 January 2018KhanspersModified description
95823view21:48, 23 January 2018KhanspersNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AKT1GeneProductENSG00000142208 (Ensembl)
AKT2GeneProductENSG00000105221 (Ensembl)
AKT3GeneProductENSG00000117020 (Ensembl)
ALKGeneProductENSG00000171094 (Ensembl)
ARAFGeneProductENSG00000078061 (Ensembl)
BADGeneProductENSG00000002330 (Ensembl)
BRAFGeneProductENSG00000157764 (Ensembl)
BUB1B-PAK6GeneProductENSG00000259288 (Ensembl)
C8orf34GeneProductENSG00000165084 (Ensembl)
CBLGeneProductENSG00000110395 (Ensembl)
CDC42GeneProductENSG00000070831 (Ensembl)
CDKN1AGeneProductENSG00000124762 (Ensembl)
CRKGeneProductENSG00000167193 (Ensembl)
CRKLGeneProductENSG00000099942 (Ensembl)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
DAGMetaboliteCHEBI:18035 (ChEBI)
ETS1GeneProductENSG00000134954 (Ensembl)
GAB1GeneProductENSG00000109458 (Ensembl)
GRB2GeneProductENSG00000177885 (Ensembl)
HGFGeneProductENSG00000019991 (Ensembl)
HRASGeneProductENSG00000174775 (Ensembl)
INSL3GeneProductENSG00000248099 (Ensembl)
IP3MetaboliteCHEBI:84244 (ChEBI)
JAK3GeneProductENSG00000105639 (Ensembl)
JUNGeneProductENSG00000177606 (Ensembl)
KRASGeneProductENSG00000133703 (Ensembl)
MAP2K1GeneProductENSG00000169032 (Ensembl)
MAP2K2GeneProductENSG00000126934 (Ensembl)
MAPK1GeneProductENSG00000100030 (Ensembl)
MAPK3GeneProductENSG00000102882 (Ensembl)
MAPK8GeneProductENSG00000107643 (Ensembl)
METGeneProduct4233 (Entrez Gene)
NRASGeneProductENSG00000213281 (Ensembl)
PAK1GeneProductENSG00000149269 (Ensembl)
PAK2GeneProductENSG00000180370 (Ensembl)
PAK3GeneProductENSG00000077264 (Ensembl)
PAK4GeneProductENSG00000130669 (Ensembl)
PAK5GeneProductENSG00000101349 (Ensembl)
PAK6GeneProductENSG00000137843 (Ensembl)
PIK3CAGeneProductENSG00000121879 (Ensembl)
PIK3CBGeneProductENSG00000051382 (Ensembl)
PIK3CDGeneProductENSG00000171608 (Ensembl)
PIK3R1GeneProductENSG00000145675 (Ensembl)
PIK3R2GeneProductENSG00000105647 (Ensembl)
PIK3R3GeneProductENSG00000117461 (Ensembl)
PIP3MetaboliteCHEBI:16618 (ChEBI)
PKCGeneProduct
PLCG1GeneProductENSG00000124181 (Ensembl)
PRCCGeneProductENSG00000143294 (Ensembl)
PTK2GeneProductENSG00000169398 (Ensembl)
PTPN11GeneProductENSG00000179295 (Ensembl)
PTPsGeneProduct
RAC1GeneProductENSG00000136238 (Ensembl)
RAF1GeneProductENSG00000132155 (Ensembl)
RAP1AGeneProductENSG00000116473 (Ensembl)
RAP1BGeneProductENSG00000127314 (Ensembl)
RAPGEF1GeneProductENSG00000107263 (Ensembl)
RPL11GeneProductENSG00000142676 (Ensembl)
SOS1GeneProductENSG00000115904 (Ensembl)
SOS2GeneProductENSG00000100485 (Ensembl)
SRCGeneProductENSG00000197122 (Ensembl)
STAT3GeneProductENSG00000168610 (Ensembl)
STRNGeneProductENSG00000115808 (Ensembl)
TCEB3GeneProductENSG00000011007 (Ensembl)
TFE3GeneProductENSG00000068323 (Ensembl)
VEGFGeneProduct
VEGFRGeneProduct
foretinibMetaboliteQ5469311 (Wikidata)
tivantinibMetaboliteQ17123902 (Wikidata)

Annotated Interactions

No annotated interactions

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