ACAP4 protein cooperates with Grb2 protein to orchestrate epidermal growth factor-stimulated integrin β1 recycling in cell migration

J Biol Chem. 2011 Dec 23;286(51):43735-47. doi: 10.1074/jbc.M111.278770. Epub 2011 Oct 25.

Abstract

ARF6 GTPase is an important regulator of membrane trafficking and actin-based cytoskeleton dynamics active at the leading edge of migrating cells. The integrin family heterodimeric transmembrane proteins serve as major receptors for extracellular matrix proteins, which play essential roles in cell adhesion and migration. Our recent proteomic analyses of ARF6 effectors have identified a novel ARF6 GTPase-activating protein, ACAP4, essential for EGF-induced cell migration. However, molecular mechanisms underlying ACAP4-mediated cell migration have remained elusive. Here, we show that ACAP4 regulates integrin β1 dynamics during EGF-stimulated cell migration by interaction with Grb2. Our biochemical study shows that EGF stimulation induces phosphorylation of tyrosine 733, which enables ACAP4 to bind Grb2. This interaction of ACAP4 with Grb2 regulates integrin β1 recycling to the plasma membrane. Importantly, knockdown of ACAP4 by siRNA or overexpression of ACAP4 decreased recycling of integrin β1 to the plasma membrane and reduced integrin-mediated cell migration. Taken together, these results suggest a novel function for ACAP4 in the regulation of cell migration through controlling integrin β1 dynamics.

Publication types

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

MeSH terms

  • ADP-Ribosylation Factors / chemistry*
  • Animals
  • COS Cells
  • Cell Membrane / metabolism
  • Cell Movement
  • Chlorocebus aethiops
  • Cytoskeletal Proteins / chemistry
  • Cytoskeleton / metabolism
  • Epidermal Growth Factor / metabolism
  • GRB2 Adaptor Protein / metabolism
  • GTPase-Activating Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Integrin beta1 / metabolism*
  • Integrins / chemistry
  • Neoplasm Metastasis
  • Phosphorylation
  • Tyrosine / chemistry

Substances

  • Cytoskeletal Proteins
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • GTPase-Activating Proteins
  • Integrin beta1
  • Integrins
  • ezrin
  • Tyrosine
  • Epidermal Growth Factor
  • ASAP3 protein, human
  • ADP-Ribosylation Factors
  • ADP-ribosylation factor 6