Mutant p53 drives invasion by promoting integrin recycling.
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.
Muller
Patricia A J
PA
The Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Caswell
Patrick T
PT
Doyle
Brendan
B
Iwanicki
Marcin P
MP
Tan
Ee H
EH
Karim
Saadia
S
Lukashchuk
Natalia
N
Gillespie
David A
DA
Ludwig
Robert L
RL
Gosselin
Pauline
P
Cromer
Anne
A
Brugge
Joan S
JS
Sansom
Owen J
OJ
Norman
Jim C
JC
Vousden
Karen H
KH
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*
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