Frontiers: PED/PEA-15, a multifunctional protein controlling cell survival and glucose metabolism.

PED/PEA-15 is a 15 kDa ubiquitously expressed protein implicated in a number of fundamental cellular functions, including apoptosis, proliferation and glucose metabolism. PED/PEA-15 lacks enzymatic function and mainly serves as a molecular adaptor. PED/PEA-15 is an endogenous substrate for protein kinase C (PKC), calcium/calmodulin-dependent protein kinase II (CAM kinase II) and Akt. In particular, PKC phosphorylates PED/PEA-15 at Ser104 and CAM kinase II or Akt at Ser116, modifying its stability. Evidence obtained over the past ten years has indicated that PED/PEA-15 regulates cell survival by interfering with both intrinsic and extrinsic apoptotic pathways. In addition, it may also control cell proliferation, by interfering with ERK1/2-mediated pathways. Indeed, PED/PEA-15 has been identified as an ERK1/2 interactor, which modifies its subcellular localization and targeting to a specific subset of substrates. Increased PED/PEA-15 levels may affect tumorigenesis and cancer progression as well as sensitivity to anti-cancer agents. Moreover, PED/PEA-15 affects astrocyte motility and increases susceptibility to skin carcinogenesis in vivo. PED/PEA-15 expression is regulated at the transcriptional and the post-translational levels. Increased PED/PEA-15 expression has been identified in individuals with type 2 diabetes early during the natural history of the disease. Evidence generated over the past ten years indicated that this defect contributes to altering glucose tolerance by impairing insulin action and insulin secretion and might play a role in the development of diabetes-associated neurological disorders. Strategies are being devised to target key signaling events in PED/PEA-15 action aiming at improving glucose tolerance and at facilitating cancer cell death.