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

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.

• Authors: Annika Wolf, Katrin Rietscher, Markus Glaß, Stefan Hüttelmaier, Mike Schutkowski, Christian Ihling, Andrea Sinz, Aileen Wingenfeld, Andrej Mun, Mechthild Hatzfeld
• Journal: Journal of cell science (J Cell Sci) Vol. 126 Issue Pt 8 Pg. 1832-44 (Apr 15 2013) ISSN: 1477-9137 [Electronic] England
• PMID: 23444369 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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