Age-related decline in Ras/ERK mitogen-activated protein kinase cascade is linked 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 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 Ras 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.
Hutter
D
D
Laboratory of Biological Chemistry, National Institute on Aging, Gerontology Research Center, Baltimore, Maryland 21224, USA.
Yo
Y
Y
Chen
W
W
Liu
P
P
Holbrook
N J
NJ
Roth
G S
GS
Liu
Y
Y
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D008099:Liver / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D011506:Proteins; D014443:Tyrosine; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins