Abstract
Phosphoprotein enriched in astrocytes, 15 KDa (PEA-15), a ubiquitously expressed small protein in all mammals, is known for decades for its potent interactions with various protein partners along distinct biological pathways. Most notable interacting partners of PEA-15 include extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the mitogen activated protein kinase (MAPK) pathway, the Fas-associated death domain (FADD) protein involving in the formation of the death-inducing signaling complex (DISC), and the phospholipase D1 (PLD1) affecting the insulin sensitivity. However, the actual cellular functions of PEA-15 are still mysterious, and the question why this protein is expressed in almost all cell and tissue types remains unanswered. Here we synthesize the most recent structural, biological, and clinical studies on PEA-15 with emphases on its anti-apoptotic, anti-proliferative, and anti-inflammative properties, and propose a converged protective role of PEA-15 that maintains the balance of death and survival in different cell types. Under conditions that this delicate balance is unsustainable, PEA-15 may become pathological and lead to various diseases, including cancers and diabetes. Targeting PEA-15 interactions, or the use of PEA-15 protein as therapeutics, may provide a wider window of opportunities to treat these diseases.
Highlights
When PEA-15 was first discovered two decades ago, it was recognized as an endogenous substrate of protein kinase C (PKC) and highly enriched in the astrocytes [1]
mitogen-activated protein (MAP) kinase signaling pathway is central in regulating cell proliferation, cell differentiation, and apoptosis, and the localization of extracellular signal-regulated kinase 1 and 2 (ERK1/2) essentially determines the fate of cells [37]
In colorectal carcinoma (CRC), the expression of PEA-15 was reported to be significantly associated with pathological T stadium, which is defined by the extent of tumor invasion into the colonic wall, suggesting a negative relationship between PEA-15 expression and grade of malignancy [46]
Summary
When PEA-15 (phosphoprotein enriched in astrocytes, 15 KDa) was first discovered two decades ago, it was recognized as an endogenous substrate of protein kinase C (PKC) and highly enriched in the astrocytes [1]. PEA-15 was found to inhibit Fas/TNF (tumor necrosis factor)-α induced apoptosis by binding to the adapter protein FADD (Fas-associated death domain) and blocking the recruitment and activation of caspase-8 [10,11,12]. PEA-15 binding to ERK1/2 blocks plasma membrane association of ERK and prevents threonine phosphorylation of fibroblast receptor substrate 2α (FRS2α). This action prolongs fibroblast growth factor (FGF)-induced tyrosine phosphorylation of FRS2α that sustains MEK and ERK activation, while inhibits the transcriptional activities of ERK1/2 [15]. The underlying mechanisms involving PEA-15 under various conditions will be discussed
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