RGD Reference Report - Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development. - Rat Genome Database

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Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development.

Authors: Khamzina, L  Gruppuso, PA  Wands, JR 
Citation: Khamzina L, etal., Gastroenterology 2003 Aug;125(2):572-85.
RGD ID: 1299201
Pubmed: PMID:12891559   (View Abstract at PubMed)

BACKGROUND & AIMS: The insulin growth factor signal transduction pathway is an important regulator of adult hepatocyte proliferation. The purpose of this study was to determine the roles of the insulin receptor substrate (IRS-1 and IRS-2)-mediated growth cascades in rapidly growing fetal rat liver. METHODS: We determined the expression and tyrosyl phosphorylation of the insulin receptor beta subunit (IRbeta), IRS-1 and IRS-2, the binding of phosphatidylinositol 3-kinase (PI3K), and activation of the mitogen-activated protein kinase (MAPK) pathway in the presence or absence of insulin stimulation in vivo during development and in the adult liver. In addition, activation of other downstream components including PI3K, Akt, GSK3beta, Bad, and p70S6 kinase was studied. RESULTS: We observed reduced expression and tyrosyl phosphorylation of IRS-1 in the fetal liver compared with the adult liver. These developmental changes resulted in a lack of sensitivity to insulin stimulation and subsequent downstream activation of the PI3K and MAPK cascades until the postneonatal period. In contrast, there was a high level of IRS-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust PI3K binding and activation, which may enhance hepatocyte survival during the rapid growth phase of the liver. CONCLUSIONS: The IRS-1 signal transduction pathway does not play a major role in fetal liver growth because IRS-2 functions as the major insulin responsive molecule in early development. However, insulin-mediated IRS-1/MAPK cascade activation contributes to growth in the adult.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
InsrRatinsulin receptor signaling pathway  IDA  RGD 
Irs2Ratinsulin receptor signaling pathway  IMP  RGD 
InsrRatprotein autophosphorylation  IDA  RGD 
InsrRatprotein phosphorylation  IDA  RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Objects Annotated

Genes (Rattus norvegicus)
Grb2  (growth factor receptor bound protein 2)
Insr  (insulin receptor)
Irs1  (insulin receptor substrate 1)
Irs2  (insulin receptor substrate 2)
Pik3r1  (phosphoinositide-3-kinase regulatory subunit 1)
Ptpn11  (protein tyrosine phosphatase, non-receptor type 11)
Sos1  (SOS Ras/Rac guanine nucleotide exchange factor 1)
Sos2  (SOS Ras/Rho guanine nucleotide exchange factor 2)

Genes (Mus musculus)
Grb2  (growth factor receptor bound protein 2)
Insr  (insulin receptor)
Irs2  (insulin receptor substrate 2)
Pik3r1  (phosphoinositide-3-kinase regulatory subunit 1)
Ptpn11  (protein tyrosine phosphatase, non-receptor type 11)
Sos1  (SOS Ras/Rac guanine nucleotide exchange factor 1)
Sos2  (SOS Ras/Rho guanine nucleotide exchange factor 2)

Genes (Homo sapiens)
GRB2  (growth factor receptor bound protein 2)
INSR  (insulin receptor)
IRS2  (insulin receptor substrate 2)
PIK3R1  (phosphoinositide-3-kinase regulatory subunit 1)
PTPN11  (protein tyrosine phosphatase non-receptor type 11)
SOS1  (SOS Ras/Rac guanine nucleotide exchange factor 1)
SOS2  (SOS Ras/Rho guanine nucleotide exchange factor 2)


Additional Information