PMID- 12774026
OWN - NLM
STAT- MEDLINE
DCOM- 20030618
LR  - 20111117
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 37
IP  - 6
DP  - 2003 Jun
TI  - Insulin receptor substrate-4 signaling in quiescent rat hepatocytes and in 
      regenerating rat liver.
PG  - 1461-9
AB  - This study was designed to characterize insulin receptor substrate-4 (IRS-4) in 
      isolated rat hepatocytes and to examine its role in liver regeneration. 
      Subcellular fractionation revealed that 85% of IRS-4 is located at isolated 
      hepatocyte plasma membranes. The distribution of IRS-4 among intracellular 
      compartments remained unchanged in insulin-stimulated cells. Two bands 
      corresponding to 145 and 138 kd were observed in immunoblotting experiments. 
      Immunoprecipitation of hepatocyte lysates with a highly specific antibody against 
      IRS-4 led to an insulin and insulin-like growth factor 1 (IGF-1)-dependent 
      increase in phosphotyrosine residues of the 145-kd band. IRS-4 was found to be 
      associated with Src homology 2 (SH2) domain-containing proteins 
      (phosphatidylinositol 3-kinase [PI 3-kinase] and Src homology phosphatase 
      [SHP-2]) and with protein kinase C zeta (PKC zeta). Insulin and IGF-1 elicited a 
      rapid and dose-dependent binding of these 3 proteins to IRS-4. These data suggest 
      that IRS-4 is insulin-/IGF-1-activated by phosphorylation and not by 
      translocation, inducing the recruitment of SH2 domain-containing proteins and PKC 
      zeta to the membrane. To evaluate the possible role of IRS-4 in liver 
      regeneration, we also examined this system after partial hepatectomy (PH). One 
      day after PH, IRS-1 expression increased, consistent with a stimulatory role in 
      the regenerative process, whereas it decreased 7 days after liver resection. This 
      drastic IRS-1 depletion occurred at the expense of increased IRS-2 and IRS-4 
      expression 7 days after PH. In addition, at this period of time after surgery, 
      the in vivo insulin stimulation of remnant rat livers showed an increase in 
      IRS-4/PI 3-kinase association. Given that 1 and 7 days after PH isolated 
      hepatocytes responded similarly to insulin in terms of induced cell 
      proliferation, a compensatory role is proposed for IRS-2/4 induction. In 
      conclusion, IRS-4 is activated by insulin and IGF-1-like IRS-1 in rat 
      hepatocytes, and the induced expression of IRS-4 is a compensatory mechanism that 
      plays a role in conditions of liver regeneration.
FAU - Escribano, Oscar
AU  - Escribano O
AD  - Unidad de Toxicologia Molecular Hepatica, Departamento de Bioquimica y Biologia 
      Molecular, Universidad de Alcala, Alcala de Henares, Spain.
FAU - Fernandez-Moreno, Maria Dolores
AU  - Fernandez-Moreno MD
FAU - Zueco, Jose Antonio
AU  - Zueco JA
FAU - Menor, Cesar
AU  - Menor C
FAU - Fueyo, Jesus
AU  - Fueyo J
FAU - Ropero, Rosa Maria
AU  - Ropero RM
FAU - Diaz-Laviada, Ines
AU  - Diaz-Laviada I
FAU - Roman, Irene D
AU  - Roman ID
FAU - Guijarro, Luis G
AU  - Guijarro LG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (IRS4 protein, rat)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Irs1 protein, rat)
RN  - 0 (Irs2 protein, rat)
RN  - 0 (Phosphoproteins)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.10.1 (Receptor, Insulin)
SB  - IM
MH  - Animals
MH  - Cell Division/drug effects
MH  - Hepatocytes/cytology/*metabolism
MH  - Insulin/pharmacology
MH  - Insulin Receptor Substrate Proteins
MH  - Insulin-Like Growth Factor I/pharmacology
MH  - Intracellular Signaling Peptides and Proteins
MH  - Liver Regeneration/*physiology
MH  - Male
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation/drug effects
MH  - Precipitin Tests
MH  - Rats
MH  - Rats, Wistar
MH  - Receptor, Insulin/metabolism
MH  - *Signal Transduction
MH  - Subcellular Fractions/metabolism
MH  - Tissue Distribution
EDAT- 2003/05/30 05:00
MHDA- 2003/06/19 05:00
CRDT- 2003/05/30 05:00
PHST- 2003/05/30 05:00 [pubmed]
PHST- 2003/06/19 05:00 [medline]
PHST- 2003/05/30 05:00 [entrez]
AID - S0270913903003409 [pii]
AID - 10.1053/jhep.2003.50245 [doi]
PST - ppublish
SO  - Hepatology. 2003 Jun;37(6):1461-9. doi: 10.1053/jhep.2003.50245.