PMID- 10092613
OWN - NLM
STAT- MEDLINE
DCOM- 19990427
LR  - 20220309
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 14
DP  - 1999 Apr 2
TI  - Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an 
      Akt/phosphatidylinositol 3-kinase pathway.
PG  - 9351-6
AB  - Serine/threonine phosphorylation of insulin receptor substrate 1 (IRS-1) has been 
      implicated as a negative regulator of insulin signaling. Prior studies have 
      indicated that this negative regulation by protein kinase C involves the 
      mitogen-activated protein kinase and phosphorylation of serine 612 in IRS-1. In 
      the present studies, the negative regulation by platelet-derived growth factor 
      (PDGF) was compared with that induced by endothelin-1, an activator of protein 
      kinase C. In contrast to endothelin-1, the inhibitory effects of PDGF did not 
      require mitogen-activated protein kinase or the phosphorylation of serine 612. 
      Instead, three other serines in the phosphorylation domain of IRS-1 (serines 632, 
      662, and 731) were required for the negative regulation by PDGF. In addition, the 
      PDGF-activated serine/threonine kinase called Akt was found to inhibit insulin 
      signaling. Moreover, this inhibition required the same IRS-1 serine residues as 
      the inhibition by PDGF. Finally, the negative regulatory effects of PDGF and Akt 
      were inhibited by rapamycin, an inhibitor of the mammalian target of rapamycin 
      (mTOR), one of the downstream targets of Akt. These studies implicate the 
      phosphatidylinositol 3-kinase/Akt kinase cascade as an additional negative 
      regulatory pathway for the insulin signaling cascade.
FAU - Li, J
AU  - Li J
AD  - Department of Molecular Pharmacology, Stanford University School of Medicine, 
      Stanford, California 94305, USA.
FAU - DeFea, K
AU  - DeFea K
FAU - Roth, R A
AU  - Roth RA
LA  - eng
GR  - DK 34926/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Endothelin-1)
RN  - 0 (Flavonoids)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - 3T3 Cells
MH  - Adipocytes/drug effects/metabolism
MH  - Animals
MH  - Endothelin-1/*pharmacology
MH  - Flavonoids/pharmacology
MH  - Insulin/pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Platelet-Derived Growth Factor/pharmacology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - *Proto-Oncogene Proteins
MH  - Proto-Oncogene Proteins c-akt
MH  - Sirolimus/pharmacology
MH  - Tyrosine/*metabolism
EDAT- 1999/03/27 00:00
MHDA- 1999/03/27 00:01
CRDT- 1999/03/27 00:00
PHST- 1999/03/27 00:00 [pubmed]
PHST- 1999/03/27 00:01 [medline]
PHST- 1999/03/27 00:00 [entrez]
AID - S0021-9258(19)87262-9 [pii]
AID - 10.1074/jbc.274.14.9351 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Apr 2;274(14):9351-6. doi: 10.1074/jbc.274.14.9351.