Role of IRS-2 in insulin and cytokine signalling

• Published in: Nature (London) 1995-09, Vol.377 (6545), p.173-177
• Main Authors: Sun, Xiao Jian, Wang, Ling-Mei, Zhang, Yitao, Yenush, Lynne, Myers Jr, Martin G, Glasheen, Erin, Lane, William S, Pierce, Jacalyn H, White, Morris F
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Biological and medical sciences; Blood Proteins - chemistry; Cell Line; Cellular biology; Cytokines - physiology; Fundamental and applied biological sciences. Psychology; Genes. Genome; Hormones; Humanities and Social Sciences; Humans; Insulin; Insulin - physiology; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; letter; Mice; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; multidisciplinary; Phosphoproteins - physiology; Phosphorylation; Proteins; Rats; Science; Science (multidisciplinary); Sequence Homology, Amino Acid; Signal Transduction - physiology; Tumor Cells, Cultured
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/377173a0

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 1–7 . It regulates gene expression and stimulates mitogenesis, and appears to mediate insulin/1GF-1-stimulated glucose transport 8 . Thus, survival of the IRS-1 −7− mouse with only mild resistance to insulin was surprising9'10. 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 phos-photyrosine-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 11 , and may be essential for signalling by several receptor systems.