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Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD.
Biochem J. 2005 Sep 15; 390(Pt 3):729-35.BJ

Abstract

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.

Authors+Show Affiliations

Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15916534

Citation

Renganathan, Hemamalini, et al. "Phosphorylation of PEA-15 Switches Its Binding Specificity From ERK/MAPK to FADD." The Biochemical Journal, vol. 390, no. Pt 3, 2005, pp. 729-35.
Renganathan H, Vaidyanathan H, Knapinska A, et al. Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD. Biochem J. 2005;390(Pt 3):729-35.
Renganathan, H., Vaidyanathan, H., Knapinska, A., & Ramos, J. W. (2005). Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD. The Biochemical Journal, 390(Pt 3), 729-35.
Renganathan H, et al. Phosphorylation of PEA-15 Switches Its Binding Specificity From ERK/MAPK to FADD. Biochem J. 2005 Sep 15;390(Pt 3):729-35. PubMed PMID: 15916534.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD. AU - Renganathan,Hemamalini, AU - Vaidyanathan,Hema, AU - Knapinska,Anna, AU - Ramos,Joe W, PY - 2005/5/27/pubmed PY - 2006/1/19/medline PY - 2005/5/27/entrez SP - 729 EP - 35 JF - The Biochemical journal JO - Biochem. J. VL - 390 IS - Pt 3 N2 - 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. SN - 1470-8728 UR - https://www.unboundmedicine.com/medline/citation/15916534/Phosphorylation_of_PEA_15_switches_its_binding_specificity_from_ERK/MAPK_to_FADD_ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BJ20050378 DB - PRIME DP - Unbound Medicine ER -