Novel regulatory roles for protein phosphatase-2A in the islet beta cell

Protein phosphorylation constitutes one of the key signaling steps in physiological insulin secretion. The phosphorylation status of a given protein represents the balance of the activities of protein kinases and phosphatases, which induce the addition and removal of phosphate from that protein, respectively. Although several extant studies were focused on the identification and characterization of protein kinases in islets, relatively little information is available on the localization and regulation of protein phosphatases in beta cells. Emerging evidence implicates protein phosphatase 2A (PP2A) in the phenomenon of insulin secretion. The three principal objectives of this commentary are to: (i) review the existing evidence, which suggests regulation, by glucose and other insulin secretagogues, of PP2A in the beta cell; (ii) discuss the experimental evidence, which implicates PP2A-like enzymes in the dephosphorylation and inactivation of key beta cell phosphoprotein substrates (e.g., Akt and Bcl-2), which may be necessary for beta cell proliferation and survival, culminating in the loss of the beta cell mass; and (iii) highlight potential avenues for future research, including the development of specific pharmacological and therapeutic interventional modalities for the inhibition of specific PP2A-like phosphatases for the prevention of loss of beta cell mass leading to the onset of diabetes.