Mutant p53 triggers a dynamin-1/APPL1 endosome feedback loop that regulates β1 integrin recycling and migration

Abstract

Multiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors. We report that gain-of-function (GOF) mutant p53 expression enhances b integrin and EGF receptor recycling and increases cell migration by triggering a positive feedback loop involving the activation of dynamin-1 (Dyn1) and accumulation of a spatially-restricted subpopulation of APPL1-positive 'perimeter' endosomes. DNM1 is upregulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53.Perimeter APPL1 endosomes are required for rapid recycling of EGFR and b1 integrins and modulate Akt signaling and Dyn1 activation to create the positive feedback loop that culminates in increased focal adhesion turnover and cell migration. Thus, Dyn1-and Aktdependent perimeter APPL1 endosomes function as a nexus, integrating signaling and receptor trafficking, that can be co-opted by cancer cells for mutant p53-driven migration and invasion. 2015). Difficulties in quantitatively measuring fast recycling render this the least mechanistically understood of these trafficking pathways.

Amplifying Tumor–Stroma Communication: An Emerging Oncogenic Function of Mutant p53

“…In fact, the ability of mut-p53 to regulate endosomal dynamics and promote recycling of membrane proteins has been associated to oncogenic outcomes. Mut-p53 R175H and R273H proteins were shown to facilitate cancer cell migration and invasion by sustaining EGFR and integrin signaling, both via the Rab-coupling protein (RCP) pathway ( 40 ) and through amplifying the dynamin-1/APPL1 endosome feedback loop ( 73 ). Specifically, mut-p53 R273H induces expression of dynamin-1 (Dyn1), an endosomal protein essential for the recruitment and accumulation of the signaling scaffold APPL1 in endosomal membrane.…”