Benito M, Valverde A M, Lorenzo M
Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Int J Biochem Cell Biol. 1996 May;28(5):499-510. doi: 10.1016/1357-2725(95)00168-9.
The main source of insulin-like growth factor I (IGF-I) postnatally is the liver, under growth hormone stimulation, although IGF-I is already present in embryonic tissues and in fetal serum, when its expression is independent of growth hormone. The extracellular alpha-subunit of the IGF-I receptor (IGF-IR) contains an IGF-I binding domain, and the beta-subunit possesses tyrosine kinase activity, which is greatly enhanced when IGF-I binds to the alpha-subunit and leads to its autophosphorylation. Insulin receptor substrate 1 (IRS-1) is the most well characterized cellular substrate for IGF-I, containing at least 20 potential tyrosine phosphorylation sites. The tyrosine phosphorylated form of IRS-1 acts as a docking protein by associating SH2-containing proteins including the p85 regulatory subunit of phosphatidylinositol-3-kinase (P13-kinase), the protein tyrosine phosphatase SH-PTP2, the SH2- and SH3-containing adaptor protein Nck and the growth factor receptor-bound protein-2 (Grb2/Sem5) protein. Grb2 is found associated with mSOS, a GTP/GDP exchange factor involved in converting the inactive Ras-GDP to the active Ras-GTP. The p85 regulatory subunit of PI3-kinase can be also a direct in vitro substrate of the IGF-IR. Although IRS-1 is the major substrate of the IGF-IR, there is another early phosphotyrosine substrate termed SHC, which also activates Ras via Grb2-mSos complex. Activation of p21-Ras induces a serine/threonine kinase cascade leading to the activation of MAP-kinases. The importance of IGF-I as a mitogen throughout development has been clearly demonstrated in IGF-I and IGF-IR knockout mouse studies and also in transgenic mice over-expressing IGF-I. IGF-I is a mitogen in many cell types in culture such as T lymphocytes, chondrocytes or osteoblasts and it is considered to be a progression factor in mouse fibroblasts. IGF-I is also involved in muscle, neurons and adipogenic differentiation of mesenchymal cells. However, IGF-I induces proliferation and differentiation in fetal brown adipocytes, suggesting that both cellular processes are not necessarily mutually exclusive in fetal cells.
出生后，胰岛素样生长因子I（IGF-I）的主要来源是肝脏，它在生长激素的刺激下产生，不过IGF-I在胚胎组织和胎儿血清中就已存在，那时其表达不依赖于生长激素。IGF-I受体（IGF-IR）的细胞外α亚基含有一个IGF-I结合结构域，β亚基具有酪氨酸激酶活性，当IGF-I与α亚基结合并导致其自身磷酸化时，该活性会大大增强。胰岛素受体底物1（IRS-1）是IGF-I最具特征的细胞底物，含有至少20个潜在的酪氨酸磷酸化位点。酪氨酸磷酸化形式的IRS-1通过与含SH2的蛋白质结合而充当对接蛋白，这些蛋白质包括磷脂酰肌醇-3激酶（P13激酶）的p85调节亚基、蛋白质酪氨酸磷酸酶SH-PTP2、含SH2和SH3的衔接蛋白Nck以及生长因子受体结合蛋白2（Grb2/Sem5）蛋白。发现Grb2与mSOS相关联，mSOS是一种鸟嘌呤核苷酸交换因子，参与将无活性的Ras-GDP转化为有活性的Ras-GTP。PI3激酶的p85调节亚基也可以是IGF-IR的直接体外底物。虽然IRS-1是IGF-IR的主要底物，但还有另一种早期磷酸酪氨酸底物称为SHC，它也通过Grb2-mSos复合物激活Ras。p21-Ras的激活诱导丝氨酸/苏氨酸激酶级联反应，导致MAP激酶的激活。在IGF-I和IGF-IR基因敲除小鼠研究以及过表达IGF-I的转基因小鼠中，IGF-I作为一种有丝分裂原在整个发育过程中的重要性已得到明确证明。IGF-I在培养的许多细胞类型中是有丝分裂原，如T淋巴细胞、软骨细胞或成骨细胞，并且它被认为是小鼠成纤维细胞中的一种促进展因子。IGF-I还参与肌肉、神经元以及间充质细胞的脂肪生成分化。然而，IGF-I在胎儿棕色脂肪细胞中诱导增殖和分化，这表明在胎儿细胞中这两个细胞过程不一定相互排斥。
