title: 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: Institute of Molecular Medicine, Division of Pathobiochemistry, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany.
authors: Annika
authors: A
authors: Wolf
authors: Katrin
authors: K
authors: Rietscher
authors: Markus
authors: M
authors: Glaß
authors: Stefan
authors: S
authors: Hüttelmaier
authors: Mike
authors: M
authors: Schutkowski
authors: Christian
authors: C
authors: Ihling
authors: Andrea
authors: A
authors: Sinz
authors: Aileen
authors: A
authors: Wingenfeld
authors: Andrej
authors: A
authors: Mun
authors: Mechthild
authors: M
authors: Hatzfeld
mesh_terms: D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D013058:Mass Spectrometry; D010766:Phosphorylation; D051191:Plakophilins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques
chemical_list: D007328:Insulin; D051191:Plakophilins; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Insulin signaling; Intercellular adhesion; Phosphorylation; Plakophilin