title: Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion.
abstract: Tumour-derived mutant p53 proteins promote invasion, in part, by enhancing Rab coupling protein (RCP)-dependent receptor recycling. Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy.
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: P A J
authors.initials: PA
authors.lastname: Muller
authors.forename: A G
authors.initials: AG
authors.lastname: Trinidad
authors.forename: P
authors.initials: P
authors.lastname: Timpson
authors.forename: J P
authors.initials: JP
authors.lastname: Morton
authors.forename: S
authors.initials: S
authors.lastname: Zanivan
authors.forename: P V E
authors.initials: PV
authors.lastname: van den Berghe
authors.forename: C
authors.initials: C
authors.lastname: Nixon
authors.forename: S A
authors.initials: SA
authors.lastname: Karim
authors.forename: P T
authors.initials: PT
authors.lastname: Caswell
authors.forename: J E
authors.initials: JE
authors.lastname: Noll
authors.forename: C R
authors.initials: CR
authors.lastname: Coffill
authors.forename: D P
authors.initials: DP
authors.lastname: Lane
authors.forename: O J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: P M
authors.initials: PM
authors.lastname: Neilsen
authors.forename: J C
authors.initials: JC
authors.lastname: Norman
authors.forename: K H
authors.initials: KH
authors.lastname: Vousden
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met