Whiteman Eileen L, Chen Janine J, Birnbaum Morris J
Howard Hughes Medical Institute, Cox Institute, Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Endocrinology. 2003 Sep;144(9):3811-20. doi: 10.1210/en.2003-0480.
Insulin is unique among growth factors and hormones in its ability to control metabolic functions such as the stimulation of glucose uptake and glucose transporter (GLUT4) translocation in physiological target tissues, such as muscle and adipose cells. Nonetheless, the mechanisms underlying this specificity have remained incompletely understood, particularly in view of the ability of some growth factors to mimic insulin-dependent early signaling events. In this study, we have probed the basis of insulin specificity by overexpressing in hormone-responsive 3T3-L1 adipocytes wild-type platelet-derived growth factor (PDGF) receptor (PDGFR)-beta and selected, informative mutant receptor proteins. We show that such adipocytes overexpressing wild-type PDGFR on exposure to cognate growth factor activate glucose transport, GLUT4 translocation, and the serine-threonine protein kinase Akt/protein kinase B to a degree comparable with that produced in response to insulin. In addition, PDGF elicits the robust generation of phosphatidylinositol-3,4,5-trisphosphate in vivo in PDGFR-overexpressing 3T3-L1 adipocytes. Expression of PDGFR-beta mutant proteins demonstrates that these responses require the presence of an intact phosphatidylinositol 3-kinase (PI3K)-binding site on the overexpressed PDGF receptor. Furthermore, PDGF stimulates these effects independent of insulin receptor substrate(IRS)-1 or IRS-2 tyrosine phosphorylation or docking to activated PI3K. These data demonstrate that 1) the basis of insulin-specific glucose transport in cultured adipocytes is the low level of receptors for other growth factors and 2) in the presence of adequate receptors, PDGF is fully capable of activating glucose transport in a manner requiring PI3K and subsequent phosphatidylinositol-3,4,5-trisphosphate accumulation but independent of insulin, insulin receptor, and IRS proteins.
胰岛素在生长因子和激素中独具特色，能够控制代谢功能，比如刺激生理靶组织（如肌肉和脂肪细胞）摄取葡萄糖以及葡萄糖转运蛋白（GLUT4）易位。然而，这种特异性背后的机制仍未完全明晰，尤其是考虑到某些生长因子能够模拟胰岛素依赖的早期信号事件。在本研究中，我们通过在激素反应性3T3-L1脂肪细胞中过表达野生型血小板衍生生长因子（PDGF）受体（PDGFR）-β以及选定的、信息丰富的突变受体蛋白，探究了胰岛素特异性的基础。我们发现，此类过表达野生型PDGFR的脂肪细胞在接触同源生长因子时，会激活葡萄糖转运、GLUT4易位以及丝氨酸-苏氨酸蛋白激酶Akt/蛋白激酶B，其激活程度与胰岛素刺激产生的程度相当。此外，PDGF在过表达PDGFR的3T3-L1脂肪细胞中能够在体内强力生成磷脂酰肌醇-3,4,5-三磷酸。PDGFR-β突变蛋白的表达表明，这些反应需要过表达的PDGF受体上存在完整的磷脂酰肌醇3激酶（PI3K）结合位点。此外，PDGF刺激这些效应与胰岛素受体底物（IRS）-1或IRS-2的酪氨酸磷酸化无关，也与对接激活的PI3K无关。这些数据表明：1）培养的脂肪细胞中胰岛素特异性葡萄糖转运的基础是其他生长因子受体水平较低；2）在有足够受体存在的情况下，PDGF完全能够以一种需要PI3K及随后磷脂酰肌醇-3,4,5-三磷酸积累但独立于胰岛素、胰岛素受体和IRS蛋白的方式激活葡萄糖转运。
