PMID- 20736160
OWN - NLM
STAT- MEDLINE
DCOM- 20101130
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 45
DP  - 2010 Nov 5
TI  - New hierarchical phosphorylation pathway of the translational repressor 
      eIF4E-binding protein 1 (4E-BP1) in ischemia-reperfusion stress.
PG  - 34355-63
LID - 10.1074/jbc.M110.135103 [doi]
AB  - Eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) is a 
      translational repressor that is characterized by its capacity to bind 
      specifically to eIF4E and inhibit its interaction with eIF4G. Phosphorylation of 
      4E-BP1 regulates eIF4E availability, and therefore, cap-dependent translation, in 
      cell stress. This study reports a physiological study of 4E-BP1 regulation by 
      phosphorylation using control conditions and a stress-induced translational 
      repression condition, ischemia-reperfusion (IR) stress, in brain tissue. In 
      control conditions, 4E-BP1 was found in four phosphorylation states that were 
      detected by two-dimensional gel electrophoresis and Western blotting, which 
      corresponded to Thr(69)-phosphorylated alone, Thr(69)- and 
      Thr(36)/Thr(45)-phosphorylated, all these plus Ser(64) phosphorylation, and 
      dephosphorylation of the sites analyzed. In control or IR conditions, no 
      Thr(36)/Thr(45) phosphorylation alone was detected without Thr(69) 
      phosphorylation, and neither was Ser(64) phosphorylation without 
      Thr(36)/Thr(45)/Thr(69) phosphorylation detected. Ischemic stress induced 4E-BP1 
      dephosphorylation at Thr(69), Thr(36)/Thr(45), and Ser(64) residues, with 4E-BP1 
      remaining phosphorylated at Thr(69) alone or dephosphorylated. In the subsequent 
      reperfusion, 4E-BP1 phosphorylation was induced at Thr(36)/Thr(45) and Ser(64), 
      in addition to Thr(69). Changes in 4E-BP1 phosphorylation after IR were according 
      to those found for Akt and mammalian target of rapamycin (mTOR) kinases. These 
      results demonstrate a new hierarchical phosphorylation for 4E-BP1 regulation in 
      which Thr(69) is phosphorylated first followed by Thr(36)/Thr(45) 
      phosphorylation, and Ser(64) is phosphorylated last. Thr(69) phosphorylation 
      alone allows binding to eIF4E, and subsequent Thr(36)/Thr(45) phosphorylation was 
      sufficient to dissociate 4E-BP1 from eIF4E, which led to eIF4E-4G interaction. 
      These data help to elucidate the physiological role of 4E-BP1 phosphorylation in 
      controlling protein synthesis.
FAU - Ayuso, Maria I
AU  - Ayuso MI
AD  - Department of Investigation, Hospital Ramon y Cajal, 28034 Madrid, Spain.
FAU - Hernandez-Jimenez, Macarena
AU  - Hernandez-Jimenez M
FAU - Martin, Maria E
AU  - Martin ME
FAU - Salinas, Matilde
AU  - Salinas M
FAU - Alcazar, Alberto
AU  - Alcazar A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100824
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Carrier Proteins)
RN  - 0 (Eif4ebp1 protein, rat)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Eukaryotic Initiation Factor-4G)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Brain/*metabolism/pathology
MH  - Carrier Proteins/*metabolism
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Eukaryotic Initiation Factor-4G/metabolism
MH  - Intracellular Signaling Peptides and Proteins
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - *Protein Biosynthesis
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Reperfusion Injury/*metabolism/pathology
MH  - *Stress, Physiological
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC2966049
EDAT- 2010/08/26 06:00
MHDA- 2010/12/14 06:00
PMCR- 2010/08/24
CRDT- 2010/08/26 06:00
PHST- 2010/08/26 06:00 [entrez]
PHST- 2010/08/26 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2010/08/24 00:00 [pmc-release]
AID - S0021-9258(20)46975-3 [pii]
AID - M110.135103 [pii]
AID - 10.1074/jbc.M110.135103 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Nov 5;285(45):34355-63. doi: 10.1074/jbc.M110.135103. Epub 2010 
      Aug 24.