Chong M P, Barritt G J, Crouch M F
Department of Medical Biochemistry, Flinders University, GPO Box 2100, Adelaide, SA 5001, Australia.
Biochem Biophys Res Commun. 2004 Sep 17;322(2):535-41. doi: 10.1016/j.bbrc.2004.07.150.
Insulin is an essential hormone for cell growth and potentiates the mitogenic actions of multiple growth factors, including EGF. While potentiation has been shown to be mediated by the upregulation of the cyclin/CDK system, the upstream mechanisms of such synergy have not been elucidated. Our study has examined whether insulin could mediate synergy by enhancing early signaling events of the EGF receptor (EGFR). Tyrosine phosphorylation at the cell periphery of confluent Swiss 3T3 fibroblasts induced by EGF was potentiated by insulin within 2 min of stimulation. Insulin potentiation of EGF-mediated phosphorylation of the EGFR occurred 2 min after stimulation. EGFR transactivation by insulin was not observed. In addition, downstream mitogenic signaling events including ERK1/2 activation and Elk-1 phosphorylation were enhanced in response to insulin and EGF coadministration. This study shows mitogenic synergy between insulin and EGF can occur at the earliest signaling event, receptor phosphorylation, and independent of transactivation.
胰岛素是细胞生长所必需的激素，可增强多种生长因子（包括表皮生长因子，即EGF）的促有丝分裂作用。虽然已表明这种增强作用是由细胞周期蛋白/细胞周期蛋白依赖性激酶（cyclin/CDK）系统的上调介导的，但这种协同作用的上游机制尚未阐明。我们的研究探讨了胰岛素是否可通过增强表皮生长因子受体（EGFR）的早期信号事件来介导协同作用。在汇合的瑞士3T3成纤维细胞周边，由EGF诱导的酪氨酸磷酸化在刺激后2分钟内就被胰岛素增强。胰岛素对EGFR介导的磷酸化的增强作用在刺激后2分钟出现。未观察到胰岛素对EGFR的反式激活作用。此外，在同时给予胰岛素和EGF后，包括ERK1/2激活和Elk-1磷酸化在内的下游促有丝分裂信号事件增强。本研究表明，胰岛素和EGF之间的促有丝分裂协同作用可发生在最早的信号事件，即受体磷酸化时，且与反式激活无关。
