Age-related decline in Ras/ERK mitogen-activated protein kinase cascade is linked to a reduced association between Shc and EGF receptor

作     者：Hutter, D Yo, Y Chen, W Liu, PH Holbrook, NJ Roth, GS Liu, YS 

作者机构：NIA Biol Chem Lab Gerontol Res Ctr Baltimore MD 21224 USA NIA Cellular & Mol Biol Lab Gerontol Res Ctr Baltimore MD 21224 USA 

出 版 物：《JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES》 (J. Gerontol. Ser. A Biol. Sci. Med. Sci.)

年 卷 期：2000年第55卷第3期

页      面：B125-B134页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

主　　题：衔接蛋白质类 信号转导 细胞衰老/生理学 细胞 培养的 GRB2衔接蛋白质 肝/化学 肝/细胞学 肝/酶学 MAP激酶激酶1 MAP激酶信号系统/生理学 丝裂原活化蛋白激酶1/代谢 丝裂原激活蛋白激酶激酶类/代谢 磷酰化 蛋白质丝氨酸苏氨酸激酶/代谢 蛋白质类/代谢 大鼠 Wistar 受体 表皮生长因子/代谢 核糖体蛋白质S6激酶类/代谢 酪氨酸/代谢 ras蛋白质类/代谢 动物 男(雄)性 大鼠 

摘      要：Numerous studies have demonstrated that the proliferative capacity of cells declines with age. Using rat primary hepatocytes as a model system, we recently demonstrated that this age-related decline in the proliferative response to mitogenic stimulation is associated with decreased activities of both extracellular signal-regulated kinase (ERK) and p70 S6 kinase (p70(S6k)). To unravel the molecular basis for age-related defects in the ERK pathway, we have now characterized the upstream signaling events that occur after epidermal growth factor (EGF) stimulation in young and aged hepatocytes. As previously noted for ERK, the activities of both MEK (the kinase immediately upstream of ERK) and pas following EGF stimulation were significantly lower in aged hepatocytes, An examination of the EGF receptor (EGFR) revealed a similar amount of EGFR in the two age groups. Likewise, EGFR and Shc, an adaptor protein that plays a crucial role in linking EGFR to Ras activation, underwent tyrosine phosphorylation to a similar degree in both young and aged hepatocytes. However, in aged cells Shc was unable to form stable complexes with EGFR after EGF stimulation. Our results suggest that a decrease in the association between Shc and EGFR in aged cells underlies the age-related declines in the ERK signaling cascade and in proliferative capacity.