- IRS1
Insulin receptor substrate 1 (IRS-1) plays a key role in transmitting signals from theinsulin and insulin-like growth factor-1 (IGF-1 ) receptors to intracellular pathways PI3K / Akt and Erk MAP kinase pathways.Tyrosine phosphorylation of the insulin or IGF-1 receptors, upon extracellular ligand binding, induces the cytoplasmic binding of IRS-1 to these receptors, through its SH2 homology domains. Multiple tryosine residues of IRS-1 itself are then phosphorylated by these receptors. This enables IRS-1 to activate several signalling pathways, including the PI3K pathway and the MAP kinase pathway.
IRS-1 plays important biological function for both metabolic and mitogenic (growth promoting) pathways: mice deficent of IRS1 have only a mild diabetic phenotype, but a pronounced growth impairment, i.e. IRS-1 knockout mice only reach 50% of the weight of normal mice. IRS-1 may also play a role in cancer, as it has been shown that transgenic mice overexpressing IRS-1 develop breast cancer. [Dearth RK, Cui X, Kim HJ, Kuiatse I, Lawrence NA, Zhang X, Divisova J, Britton OL, Mohsin S, Allred DC, Hadsell DL, Lee AV. Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Mol Cell Biol. 2006 Dec;26(24):9302-14.]
Regulation of IRS-1
The cellular protein levels of IRS-1 are regulated by the
Cullin7 E3 ubiquin ligase, which targets IRS-1 for ubiquitin mediated degradation by the proteasome. [Xu X , Sarikas A, Dias-Santagata DC, Dolios G, Lafontant PJ, Tsai SC, Zhu W, Nakajima H, Nakajima HO, Field LJ, Wang R, Pan ZQ. The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation. Mol Cell. 2008;30:403-414.]PBB_Summary
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*cite journal | author=Jiang H, Harris MB, Rothman P |title=IL-4/IL-13 signaling beyond JAK/STAT. |journal=J. Allergy Clin. Immunol. |volume=105 |issue= 6 Pt 1 |pages= 1063–70 |year= 2000 |pmid= 10856136 |doi=
*cite journal | author=Bezerra RM, Chadid TT, Altemani CM, "et al." |title=Lack of Arg972 polymorphism in the IRS1 gene in Parakanã Brazilian Indians. |journal=Hum. Biol. |volume=76 |issue= 1 |pages= 147–51 |year= 2004 |pmid= 15222685 |doi=
*cite journal | author=Gibson SL, Ma Z, Shaw LM |title=Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. |journal=Cell Cycle |volume=6 |issue= 6 |pages= 631–7 |year= 2007 |pmid= 17361103 |doi=
*cite journal | author=Dearth RK, Cui X, Kim HJ, "et al." |title=Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. |journal=Cell Cycle |volume=6 |issue= 6 |pages= 705–13 |year= 2007 |pmid= 17374994 |doi=References
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