title: Mutant p53 drives invasion by promoting integrin recycling.
abstract: p53 is a tumor suppressor protein whose function is frequently lost in cancers through missense mutations within the Tp53 gene. This results in the expression of point-mutated p53 proteins that have both lost wild-type tumor suppressor activity and show gain of functions that contribute to transformation and metastasis. Here, we show that mutant p53 expression can promote invasion, loss of directionality of migration, and metastatic behavior. These activities of p53 reflect enhanced integrin and epidermal growth factor receptor (EGFR) trafficking, which depends on Rab-coupling protein (RCP) and results in constitutive activation of EGFR/integrin signaling. We provide evidence that mutant p53 promotes cell invasion via the inhibition of TAp63, and simultaneous loss of p53 and TAp63 recapitulates the phenotype of mutant p53 in cells. These findings open the possibility that blocking alpha5/beta1-integrin and/or the EGF receptor will have therapeutic benefit in mutant p53-expressing cancers.
authors.affiliation: The Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Patricia A J
authors.initials: PA
authors.lastname: Muller
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Caswell
authors.forename: Brendan
authors.initials: B
authors.lastname: Doyle
authors.forename: Marcin P
authors.initials: MP
authors.lastname: Iwanicki
authors.forename: Ee H
authors.initials: EH
authors.lastname: Tan
authors.forename: Saadia
authors.initials: S
authors.lastname: Karim
authors.forename: Natalia
authors.initials: N
authors.lastname: Lukashchuk
authors.forename: David A
authors.initials: DA
authors.lastname: Gillespie
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ludwig
authors.forename: Pauline
authors.initials: P
authors.lastname: Gosselin
authors.forename: Anne
authors.initials: A
authors.lastname: Cromer
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
authors.forename: Karen H
authors.initials: KH
authors.lastname: Vousden
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D009362:Neoplasm Metastasis; D011554:Pseudopodia / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D039081:Integrin alpha5beta1; D008565:Membrane Proteins; C488966:RAB11FIP1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors