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

We report that dynamin-1 (Dyn1) is up-regulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Dyn1 is required for the recruitment and accumulation of the signaling scaffold, APPL1, to a spatially localized subpopulation of endosomes at the cell perimeter. We developed new tools to quantify peripherally localized early endosomes and measure the rapid recycling of integrins. We report that these perimeter APPL1 endosomes modulate Akt signaling and activate Dyn1 to create a positive feedback loop required for rapid recycling of EGFR and β1 integrins, increased focal adhesion turnover, and cell migration. Thus, Dyn1- and Akt-dependent perimeter APPL1 endosomes function as a nexus that integrates signaling and receptor trafficking, which can be co-opted and amplified in mutant p53–driven cancer cells to increase migration and invasion.

Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Lakoduk, A. M., Roudot, P., Mettlen, M., Grossman, H. M., Schmid, S. L., Chen, P.-H. Tags: Cell Signaling, Trafficking, Cancer Articles Source Type: research