Abstract
Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these protein–protein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases.
Highlights
Since the initial characterisation of phosphoprotein enriched in astrocytes-15 (PEA-15) almost 20 years ago (Araujo et al, 1993; Danziger et al, 1995), the unique function of this protein in regulating intracellular pathways has become increasingly evident
We have shown that knockdown of phospholipase Cγ1 prevents the plateletderived growth factor (PDGF)-induced translocation of extracellular signal-regulated kinase 1/2 (ERK1/2) by blocking PEA-15 phosphorylation but does not prevent ERK1/2 activation (Hunter et al, 2011)
Considering the intracellular role that PEA-15 has in regulating proliferation and apoptosis, it is perhaps not surprising that, in addition to cancer, this phosphoprotein could be involved in other diseases where similar cellular processes occur
Summary
Since the initial characterisation of phosphoprotein enriched in astrocytes-15 (PEA-15) almost 20 years ago (Araujo et al, 1993; Danziger et al, 1995), the unique function of this protein in regulating intracellular pathways has become increasingly evident. Sitting at a critical signalling junction which regulates cell behaviour, PEA-15 has the potential to direct cell phenotypic modulation (Renault et al, 2003; Valmiki & Ramos, 2009). Recent studies, both biochemical and structural, have begun to further tease out the molecular mechanisms of these protein interactions in greater detail and led to an enhanced understanding of the biology of PEA-15 and its important role in many cellular processes. This review will examine, in detail, current findings with regard to PEA-15's intracellular functions It will evaluate the potential role of PEA-15 in specific disease states with a view to identifying new areas for therapeutic intervention
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