Insulin signaling via Akt2 switches plakophilin 1 function from stabilizing cell adhesion to promoting cell proliferation

J Cell Sci. 2013 Apr 15;126(Pt 8):1832-44. doi: 10.1242/jcs.118992. Epub 2013 Feb 26.

Abstract

Downregulation of adherens junction proteins is a frequent event in carcinogenesis. How desmosomal proteins contribute to tumor formation by regulating the balance between adhesion and proliferation is not well understood. The desmosomal protein plakophilin 1 can increase intercellular adhesion by recruiting desmosomal proteins to the plasma membrane or stimulate proliferation by enhancing translation rates. Here, we show that these dual functions of plakophilin 1 are regulated by growth factor signaling. Insulin stimulation induced the phosphorylation of plakophilin 1, which correlated with reduced intercellular adhesion and an increased activity of plakophilin 1 in the stimulation of translation. Phosphorylation was mediated by Akt2 at four motifs within the plakophilin 1 N-terminal domain. A plakophilin 1 phospho-mimetic mutant revealed reduced intercellular adhesion and accumulated in the cytoplasm, where it increased translation and proliferation rates and conferred the capacity of anchorage-independent growth. The cytoplasmic accumulation was mediated by the stabilization of phosphorylated plakophilin 1, which displayed a considerably increased half-life, whereas non-phosphorylated plakophilin 1 was more rapidly degraded. Our data indicate that upon activation of growth factor signaling, plakophilin 1 switches from a desmosome-associated growth-inhibiting to a cytoplasmic proliferation-promoting function. This supports the view that the deregulation of plakophilin 1, as observed in several tumors, directly contributes to hyperproliferation and carcinogenesis in a context-dependent manner.

Keywords: Akt; Insulin signaling; Intercellular adhesion; Phosphorylation; Plakophilin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / genetics
  • Cell Adhesion / physiology*
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Survival / physiology
  • HeLa Cells
  • Humans
  • Immunoprecipitation
  • Insulin / metabolism
  • Mass Spectrometry
  • Phosphorylation
  • Plakophilins / genetics
  • Plakophilins / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / physiology
  • Two-Hybrid System Techniques

Substances

  • Insulin
  • Plakophilins
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt