PMID- 9651339
OWN - NLM
STAT- MEDLINE
DCOM- 19980806
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 273
IP  - 28
DP  - 1998 Jul 10
TI  - Evidence that IRS-2 phosphorylation is required for insulin action in 
      hepatocytes.
PG  - 17491-7
AB  - Insulin receptor substrates (IRSs) are tyrosine-phosphorylated following 
      stimulation with insulin, insulin-like growth factors (IGFs), and interleukins. A 
      key question is whether different IRSs play different roles to mediate insulin's 
      metabolic and growth-promoting effects. In a novel system of insulin 
      receptor-deficient hepatocytes, insulin fails to (i) stimulate glucose 
      phosphorylation, (ii) enhance glycogen synthesis, (iii) suppress glucose 
      production, and (iv) promote mitogenesis. However, insulin's ability to induce 
      IRS-1 and gab-1 phosphorylation and binding to phosphatidylinositol (PI) 3-kinase 
      is unaffected, by virtue of the compensatory actions of IGF-1 receptors. In 
      contrast, phosphorylation of IRS-2 and generation of IRS-2/PI 3-kinase complexes 
      are markedly reduced. Thus, absence of insulin receptors selectively reduces 
      IRS-2, but not IRS-1 phosphorylation, and the impairment of IRS-2 activation is 
      associated with lack of insulin effects. To address whether phosphorylation of 
      additional IRSs is also affected, we analyzed phosphotyrosine-containing proteins 
      in PI 3-kinase immunoprecipitates from insulin-treated cells. However, these 
      experiments indicate that IRS-1 and IRS-2 are the main PI 3-kinase-bound proteins 
      in hepatocytes. These data identify IRS-2 as the main effector of both the 
      metabolic and growth-promoting actions of insulin through PI 3-kinase in 
      hepatocytes, and IRS-1 as the main substrate mediating the mitogenic actions of 
      IGF-1 receptors.
FAU - Rother, K I
AU  - Rother KI
AD  - Developmental Endocrinology Branch, NICHD, National Institutes of Health, 
      Bethesda, Maryland 20892-1862, USA.
FAU - Imai, Y
AU  - Imai Y
FAU - Caruso, M
AU  - Caruso M
FAU - Beguinot, F
AU  - Beguinot F
FAU - Formisano, P
AU  - Formisano P
FAU - Accili, D
AU  - Accili D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Irs2 protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, Insulin)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Insulin/*pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - Intracellular Signaling Peptides and Proteins
MH  - Liver/cytology/*drug effects/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Precipitin Tests
MH  - Receptor, Insulin/genetics/*metabolism
MH  - Signal Transduction
EDAT- 1998/07/04 00:00
MHDA- 1998/07/04 00:01
CRDT- 1998/07/04 00:00
PHST- 1998/07/04 00:00 [pubmed]
PHST- 1998/07/04 00:01 [medline]
PHST- 1998/07/04 00:00 [entrez]
AID - S0021-9258(18)80515-4 [pii]
AID - 10.1074/jbc.273.28.17491 [doi]
PST - ppublish
SO  - J Biol Chem. 1998 Jul 10;273(28):17491-7. doi: 10.1074/jbc.273.28.17491.