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

J Cell Biol. 2019 Jun 3;218(6):1928-1942. doi: 10.1083/jcb.201810183. Epub 2019 May 1.


Multiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors downstream of gain-of-function (GOF) mutant p53. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Adhesion
  • Cell Membrane
  • Cell Movement*
  • Dynamin I / genetics
  • Dynamin I / metabolism*
  • Endocytosis
  • Endosomes / metabolism*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Feedback, Physiological
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mutation*
  • Protein Transport
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • APPL1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Integrin beta1
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • EGFR protein, human
  • ErbB Receptors
  • Dynamin I