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

Numerous studies have demonstrated that the proliferative capacity of cells declines with age. Using rat primary hepatocytes as a model system, we rec ently demonstrated that this age-related decline in the proliferative respo nse to mitogenic stimulation is associated with decreased activities of bot h 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 e pidermal growth factor (EGF) stimulation in young and aged hepatocytes. As previously noted for ERK, the activities of both MEK (the kinase immediatel y upstream of ERK) and pas following EGF stimulation were significantly low er 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 comp lexes with EGFR after EGF stimulation. Our results suggest that a decrease in the association between Shc and EGFR in aged cells underlies the age-rel ated declines in the ERK signaling cascade and in proliferative capacity.