Cell signalling pathways that regulate proliferation and those that regulate programmed cell death (apoptosis) are co-ordinated. The proteins and mechanisms that mediate the integration of these pathways are not yet fully described. The phosphoprotein PEA-15 (phosphoprotein enriched in astrocytes) can regulate both the ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) pathway and the death receptor-initiated apoptosis pathway. This is the result of PEA-15 binding to the ERK/MAPK or the proapoptotic protein FADD (Fas-activated death domain protein) respectively. The mechanism by which binding of PEA-15 to these proteins is controlled has not been elucidated. PEA-15 is a phosphoprotein containing a Ser-104 phosphorylated by protein kinase C and a Ser-116 phosphorylated by CamKII (calcium/calmodulin-dependent protein kinase II) or AKT. Phosphorylation of Ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at Ser-116 is required for PEA-15 recruitment to the DISC (death-initiation signalling complex). Moreover, PEA-15 must be phosphorylated at Ser-116 to inhibit apoptosis. In the present study, we report that phosphorylation at Ser-104 blocks ERK binding to PEA-15 in vitro and in vivo, whereas phosphorylation at Ser-116 promotes its binding to FADD. We further characterize phospho-epitope-binding antibodies to these sites. We report that phosphorylation does not influence the distribution of PEA-15 between the cytoplasm and nucleus of the cell since all phosphorylated states are found predominantly in the cytoplasm. We propose that phosphorylation of PEA-15 acts as the switch that controls whether PEA-15 influences proliferation or apoptosis.
Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD
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Hemamalini Renganathan, Hema Vaidyanathan, Anna Knapinska, Joe W. Ramos; Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD. Biochem J 15 September 2005; 390 (3): 729–735. doi: https://doi.org/10.1042/BJ20050378
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