CLIC4 regulates cell adhesion and β1 integrin trafficking

J Cell Sci. 2014 Dec 15;127(Pt 24):5189-203. doi: 10.1242/jcs.150623. Epub 2014 Oct 24.


Chloride intracellular channel protein 4 (CLIC4) exists in both soluble and membrane-associated forms, and is implicated in diverse cellular processes, ranging from ion channel formation to intracellular membrane remodeling. CLIC4 is rapidly recruited to the plasma membrane by lysophosphatidic acid (LPA) and serum, suggesting a possible role for CLIC4 in exocytic-endocytic trafficking. However, the function and subcellular target(s) of CLIC4 remain elusive. Here, we show that in HeLa and MDA-MB-231 cells, CLIC4 knockdown decreases cell-matrix adhesion, cell spreading and integrin signaling, whereas it increases cell motility. LPA stimulates the recruitment of CLIC4 to β1 integrin at the plasma membrane and in Rab35-positive endosomes. CLIC4 is required for both the internalization and the serum- or LPA-induced recycling of β1 integrin, but not for EGF receptor trafficking. Furthermore, we show that CLIC4 suppresses Rab35 activity and antagonizes Rab35-dependent regulation of β1 integrin trafficking. Our results define CLIC4 as a regulator of Rab35 activity and serum- and LPA-dependent integrin trafficking.

Keywords: CLIC4; Cell adhesion; Integrin trafficking; Lysophosphatidic acid; Rab35.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / drug effects
  • Cell Movement / drug effects
  • Chloride Channels / metabolism*
  • Endocytosis / drug effects
  • Endosomes / drug effects
  • Endosomes / metabolism
  • ErbB Receptors / metabolism
  • Focal Adhesions / drug effects
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Integrin beta1 / metabolism*
  • Lysophospholipids / pharmacology
  • Protein Transport / drug effects
  • Serum
  • Signal Transduction / drug effects
  • rab GTP-Binding Proteins / metabolism


  • CLIC4 protein, human
  • Chloride Channels
  • Integrin beta1
  • Lysophospholipids
  • ErbB Receptors
  • RAB35 protein, human
  • rab GTP-Binding Proteins
  • lysophosphatidic acid