Role of IRS-2 in insulin and cytokine signalling.
The protein IRS-1 acts as an interface between signalling proteins with Src-homology-2 domains (SH2 proteins) and the receptors for insulin, IGF-1, growth hormone, several interleukins (IL-4, IL-9, IL-13) and other cytokines. It regulates gene expression and stimulates mitogenesis, and appears to mediate insulin/IGF-1-stimulated glucose transport. Thus, survival of the IRS-1-/- mouse with only mild resistance to insulin was surprising. This dilemma is provisionally resolved with our discovery of a second IRS-signalling protein. We purified and cloned a likely candidate called 4PS from myeloid progenitor cells and, because of its resemblance to IRS-1, we designate it IRS-2. Alignment of the sequences of IRS-2 and IRS-1 revealed a highly conserved amino terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding domain, and a poorly conserved carboxy terminus containing several tyrosine phosphorylation motifs. IRS-2 is expressed in many cells, including tissues from IRS-1-/- mice, and may be essential for signalling by several receptor systems.
Sun
X J
XJ
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Wang
L M
LM
Zhang
Y
Y
Yenush
L
L
Myers
M G
MG
Glasheen
E
E
Lane
W S
WS
Pierce
J H
JH
White
M F
MF
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001798:Blood Proteins / Q000737:chemistry; D002460:Cell Line; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D001798:Blood Proteins; D016207:Cytokines; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; D010750:Phosphoproteins; C039077:platelet protein P47