PMID- 18927238
OWN - NLM
STAT- MEDLINE
DCOM- 20090306
LR  - 20211203
IS  - 0888-8809 (Print)
IS  - 1944-9917 (Electronic)
IS  - 0888-8809 (Linking)
VI  - 22
IP  - 12
DP  - 2008 Dec
TI  - Interplay and effects of temporal changes in the phosphorylation state of 
      serine-302, -307, and -318 of insulin receptor substrate-1 on insulin action in 
      skeletal muscle cells.
PG  - 2729-40
LID - 10.1210/me.2008-0102 [doi]
AB  - Transduction of the insulin signal is mediated by multisite Tyr and Ser/Thr 
      phosphorylation of the insulin receptor substrates (IRSs). Previous studies on 
      the function of single-site phosphorylation, particularly phosphorylation of 
      Ser-302, -307, and -318 of IRS-1, showed attenuating as well as enhancing effects 
      on insulin action. In this study we investigated a possible cross talk of these 
      opposedly acting serine residues in insulin-stimulated skeletal muscle cells by 
      monitoring phosphorylation kinetics, and applying loss of function, gain of 
      function, and combination mutants of IRS-1. The phosphorylation at Ser-302 was 
      rapid and transient, followed first by Ser-318 phosphorylation and later by 
      phosphorylation of Ser-307, which remained elevated for 120 min. Mutation of 
      Ser-302 to alanine clearly reduced the subsequent protein kinase C-zeta-mediated 
      Ser-318 phosphorylation. The Ser-307 phosphorylation was independent of Ser-302 
      and/or Ser-318 phosphorylation status. The functional consequences of these 
      phosphorylation patterns were studied by the expression of IRS-1 mutants. The 
      E302A307E318 mutant simulating the early phosphorylation pattern resulted in a 
      significant increase in Akt and glycogen synthase kinase 3 phosphorylation. 
      Furthermore, glucose uptake was enhanced. Because the down-regulation of the 
      insulin signal was not affected, this phosphorylation pattern seems to be 
      involved in the enhancement but not in the termination of the insulin signal. 
      This enhancing effect was completely absent when Ser-302 was unphosphorylated and 
      Ser-307 was phosphorylated as simulated by the A302E307E318 mutant. 
      Phospho-Ser-318, sequentially phosphorylated at least by protein kinase C-zeta 
      and a mammalian target of rapamycin/raptor-dependent kinase, was part of the 
      positive as well as of the subsequent negative phosphorylation pattern. Thus we 
      conclude that insulin stimulation temporally generates different phosphorylation 
      statuses of the same residues that exert different functions in insulin 
      signaling.
FAU - Weigert, Cora
AU  - Weigert C
AD  - Division of Clinical Chemistry and Pathobiochemistry, University Hospital of 
      Tubingen, Tubingen, Germany.
FAU - Kron, Matthias
AU  - Kron M
FAU - Kalbacher, Hubert
AU  - Kalbacher H
FAU - Pohl, Ann Kathrin
AU  - Pohl AK
FAU - Runge, Heike
AU  - Runge H
FAU - Haring, Hans-Ulrich
AU  - Haring HU
FAU - Schleicher, Erwin
AU  - Schleicher E
FAU - Lehmann, Rainer
AU  - Lehmann R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081016
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Carrier Proteins)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (protein kinase C zeta)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/metabolism/physiology
MH  - Cells, Cultured
MH  - Glucose/metabolism
MH  - Insulin/*pharmacology
MH  - Insulin Receptor Substrate Proteins/chemistry/*metabolism/physiology
MH  - Kinetics
MH  - Mice
MH  - Models, Biological
MH  - Muscle Fibers, Skeletal/*drug effects/metabolism
MH  - Phosphorylation/drug effects/physiology
MH  - Phosphotransferases (Alcohol Group Acceptor)/metabolism/physiology
MH  - Protein Kinase C/metabolism/physiology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Serine/*metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
PMC - PMC5419409
EDAT- 2008/10/18 09:00
MHDA- 2009/03/07 09:00
PMCR- 2009/12/01
CRDT- 2008/10/18 09:00
PHST- 2008/10/18 09:00 [pubmed]
PHST- 2009/03/07 09:00 [medline]
PHST- 2008/10/18 09:00 [entrez]
PHST- 2009/12/01 00:00 [pmc-release]
AID - me.2008-0102 [pii]
AID - 10.1210/me.2008-0102 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2008 Dec;22(12):2729-40. doi: 10.1210/me.2008-0102. Epub 2008 Oct 
      16.