Sun X J, Wang L M, Zhang Y, Yenush L, Myers M G, Glasheen E, Lane W S, Pierce J H, White M F
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Nature. 1995 Sep 14;377(6545):173-7. 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. 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.
蛋白质IRS-1作为具有Src同源2结构域的信号蛋白（SH2蛋白）与胰岛素、IGF-1、生长激素、几种白细胞介素（IL-4、IL-9、IL-13）及其他细胞因子受体之间的接口。它调节基因表达并刺激有丝分裂，似乎还介导胰岛素/IGF-1刺激的葡萄糖转运。因此，IRS-1基因敲除小鼠仅对胰岛素有轻度抵抗却能存活，这令人惊讶。随着我们发现第二种IRS信号蛋白，这一困境暂时得到了解决。我们从髓系祖细胞中纯化并克隆了一种名为4PS的可能候选蛋白，由于它与IRS-1相似，我们将其命名为IRS-2。IRS-2和IRS-1序列比对显示，其氨基末端高度保守，包含一个普列克底物蛋白同源结构域和一个磷酸酪氨酸结合结构域，而羧基末端保守性较差，包含几个酪氨酸磷酸化基序。IRS-2在许多细胞中表达，包括来自IRS-1基因敲除小鼠的组织，可能对几种受体系统的信号传导至关重要。
