On the Quest of Cellular Functions of PEA-15 and the Therapeutic Opportunities

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.

Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity

“…3 B ). The cellular functions of PEA-15 are yet to be fully elucidated, but it has been previously shown that PEA-15 can negatively regulate ERK1/2, the Fas-associated death domain, and phospholipase D1 proteins, indicating that it may have antiapoptotic, antiproliferative, and antiinflammatory properties ( 26 ). Overexpression of BCL2 has also been shown to enhance the therapeutic efficacy of tumor-specific T cells ( 27 ).…”

PEA-15 C-Terminal Tail Allosterically Modulates Death-Effector Domain Conformation and Facilitates Protein–Protein Interactions

“…The reorganization of the helices in DED is modulated by the rearrangement of hydrogen-bonding and electrostatic interactions among the polar and charged residues on the DED surface. This result is significant because it provides structural insight on the importance of phosphorylation homeostasis in affecting cellular processes and cell fate [38].…”

The protein phosphatase 4 - PEA15 axis regulates the survival of breast cancer cells

“…It is implicated in the dysregulation of many signalling pathways involved in cancer progression and tumorigenesis and it has been described to act as both a tumour suppressor and a tumour promoter, dependent on its phosphorylation status [30][31][32]. The PEA15 gene is amplified in breast cancer, as well as in other cancers [33], and the unphosphorylated form of PEA15 is more potent than the phosphorylated form in suppressing tumorigenicity in breast cancer [34]. While several kinases have been reported to be involved in the phosphorylation of PEA15 including Akt, Ca2+/calmodulin-dependent protein kinase (CaMKII) and AMP-activated protein kinase (AMPK) [35,36], the dephosphorylation of PEA15 is much less understood.…”

“…Consistent with these observations, others have reported that the non-phosphorylated form of PEA15 binds to the extracellular signal-regulated kinase 1/2 (ERK1/2), preventing its nuclear accumulation, leading to the inhibition of cell proliferation [30,31]. On the other hand, phosphorylation of PEA15 on Ser116 promotes its binding to Fas-associated death domain protein (FADD) via its DED domain, preventing FADD-mediated activation of caspases and the formation of the death inducing signalling complex (DISC), leading to the inhibition of the extrinsic apoptotic pathway [30,33,47].…”