PMID- 15916534
OWN - NLM
STAT- MEDLINE
DCOM- 20060118
LR  - 20220225
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 390
IP  - Pt 3
DP  - 2005 Sep 15
TI  - Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD.
PG  - 729-35
AB  - 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.
FAU - Renganathan, Hemamalini
AU  - Renganathan H
AD  - Department of Cell Biology and Neuroscience, Rutgers, The State University of New 
      Jersey, 604 Allison Road, Piscataway, NJ 08854, USA.
FAU - Vaidyanathan, Hema
AU  - Vaidyanathan H
FAU - Knapinska, Anna
AU  - Knapinska A
FAU - Ramos, Joe W
AU  - Ramos JW
LA  - eng
GR  - R01 CA093849/CA/NCI NIH HHS/United States
GR  - R01 CA093849-05/CA/NCI NIH HHS/United States
GR  - R56 CA093849/CA/NCI NIH HHS/United States
GR  - CA93849/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (FADD protein, human)
RN  - 0 (Fas-Associated Death Domain Protein)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (PEA15 protein, human)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Animals
MH  - Apoptosis
MH  - Apoptosis Regulatory Proteins
MH  - COS Cells
MH  - Cell Nucleus/metabolism
MH  - Cell Proliferation
MH  - Chlorocebus aethiops
MH  - Cytoplasm/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/genetics/*metabolism
MH  - Fas-Associated Death Domain Protein
MH  - Gene Expression Regulation
MH  - HeLa Cells
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - Phosphoproteins/genetics/*metabolism
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Transport
MH  - Substrate Specificity
MH  - Tetradecanoylphorbol Acetate
PMC - PMC1199667
EDAT- 2005/05/27 09:00
MHDA- 2006/01/19 09:00
PMCR- 2006/03/15
CRDT- 2005/05/27 09:00
PHST- 2005/05/27 09:00 [pubmed]
PHST- 2006/01/19 09:00 [medline]
PHST- 2005/05/27 09:00 [entrez]
PHST- 2006/03/15 00:00 [pmc-release]
AID - BJ20050378 [pii]
AID - bj3900729 [pii]
AID - 10.1042/BJ20050378 [doi]
PST - ppublish
SO  - Biochem J. 2005 Sep 15;390(Pt 3):729-35. doi: 10.1042/BJ20050378.