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

Abstract

SummaryDownregulation 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 nonphosphorylated 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.

Palmitoylation of plakophilin is required for desmosome assembly

“…8). Others have previously shown that exogenous expression of plakophilin isoforms can increase intercellular adhesion (Roberts et al, 2013;Setzer et al, 2004;Wolf et al, 2013). By contrast, expression of the Myc-tagged plakophilin palmitoylation mutants failed to increase intercellular adhesion in these cultures.…”

Desmosomes: Regulators of Cellular Signaling and Adhesion in Epidermal Health and Disease

“…For instance, Dp either supports (Gallicano et al 1998) or inhibits proliferation depending on cell type, the latter through suppression of Erk and Akt (Wan et al 2007). In turn, growth factor signaling can convert desmosomal components from adhesive to pro-proliferative functions as in the case of insulin signaling via Akt2 causing Pkp1 to promote proliferation and migration (Wolf et al 2013). Collectively, these observations suggest that the core building blocks of desmosomes are tailored to support specific functions within complex tissues and are important for controlling epidermal homeostasis.…”

Plakophilins in Desmosomal Adhesion and Signaling

“…A recent report shows how phosphorylation of PKP1 controls the distribution between its desmosomal and cytoplasmic pools and shifts the balance from an adhesion promoting function of un-phosphorylated PKP1 to a translation and proliferation promoting function of the phosphorylated form (Figure 4, [Wolf et al, 2013]). Insulin/IGF-1-signaling via the PI3K -AKT pathway induced the phosphorylation of the PKP1 head domain.…”