Melmed S, Yamashita S, Yamasaki H, Fagin J, Namba H, Yamamoto H, Weber M, Morita S, Webster J, Prager D
Department of Medicine, Cedars-Sinai Research Institute-UCLA School of Medicine 90048, USA.
Recent Prog Horm Res. 1996;51:189-215; discussion 215-6.
Insulin-like growth factor 1 (IGF-I) is a major feedback regulator of pituitary GH secretion, with defined actions occurring at both the hypothalamus and pituitary. The IGF-I gene is expressed in the anterior pituitary in a GH-dependent manner thus providing for both endocrine-as well as autocrine-mediated GH regulation. In turn, IGF-I selectively and specifically inhibits GH gene transcription and secretion, its attenuating effects on nascent GH mRNA synthesis being demonstrable within 1 h. Binding of IGF-I to its pituitary cell surface receptor is followed by rapid activation of the intrinsic tyrosine kinase activity of the receptor beta-subunit and phosphorylation of insulin receptor substrate 1 (IRS-1). Structure-function studies of the human IGF-I receptor were performed in stable, GH-secreting transfectants expressing either the cDNA encoding the wild-type (WT) human IGF receptor and exhibiting enhanced IGF-I responsiveness, or cDNAs encoding IGF-I receptor mutants and a truncated, kinase-deficient receptor (952STOP). 950Tyr situated on the submembrane receptor domain was found to be critical for transducing the IGF-I signal to the GH gene. IGF-I failed to suppress GH secretion by signalling endogenous rat IGF-I receptors when hybrid receptors were formed with kinase-deficient human receptors and rat hemi-receptors. This dominant negative effect on hormone secretion was also evidenced when mitogenic IGF-I signals were blocked in vitro and in vivo by these hybrid receptors. Using similar doses of IGF-I, the IGF-I receptor cell transfectants also demonstrated ligand-dependent activation of ERKs in pituitary cells. In conclusion, the pituitary IGF-I receptor mediates the negative feedback regulation of GH. Thus, IGF-I receptor mass may determine GH responses to malnutrition, pregnancy, and refeeding. IGF-I receptor mutations may also prove useful to abrogate the growth of IGF-I-dependent tumors. These structure-function studies of the human IGF-I receptor provide mechanistic insights into both metabolic control of the GH axis, as well as target tissue proliferative characteristics.
胰岛素样生长因子1（IGF-I）是垂体生长激素（GH）分泌的主要反馈调节因子，在下丘脑和垂体均有明确作用。IGF-I基因以前列腺素依赖性方式在前叶垂体中表达，从而实现内分泌以及自分泌介导的GH调节。反过来，IGF-I选择性且特异性地抑制GH基因转录和分泌，其对新生GH mRNA合成的衰减作用在1小时内即可显现。IGF-I与其垂体细胞表面受体结合后，会迅速激活受体β亚基的内在酪氨酸激酶活性，并使胰岛素受体底物1（IRS-1）磷酸化。在稳定分泌GH的转染细胞中进行了人IGF-I受体的结构功能研究，这些转染细胞要么表达编码野生型（WT）人IGF受体的cDNA并表现出增强的IGF-I反应性，要么表达编码IGF-I受体突变体和截短的激酶缺陷型受体（952STOP）的cDNA。位于膜下受体结构域的950Tyr被发现对于将IGF-I信号转导至GH基因至关重要。当杂合受体由激酶缺陷型人受体和大鼠半受体形成时，IGF-I无法通过内源性大鼠IGF-I受体信号传导来抑制GH分泌。当这些杂合受体在体外和体内阻断有丝分裂IGF-I信号时，也证明了对激素分泌的这种显性负效应。使用相似剂量的IGF-I，IGF-I受体细胞转染体在垂体细胞中也显示出配体依赖性的细胞外信号调节激酶（ERK）激活。总之，垂体IGF-I受体介导GH的负反馈调节。因此，IGF-I受体量可能决定GH对营养不良、妊娠和再喂养的反应。IGF-I受体突变也可能被证明有助于消除IGF-I依赖性肿瘤的生长。这些人IGF-I受体的结构功能研究为GH轴的代谢控制以及靶组织增殖特征提供了机制性见解。
