Activation of murine T-cells via phospholipase-C gamma 1-associated protein tyrosine phosphorylation is reduced with aging.
Cross-linking of the T-cell receptor (CD3) induces activation of tyrosine kinases and the subsequent phosphorylation of intracellular protein substrates. We examined whether early events in signal transduction through CD3 or CD3 x CD4 receptor ligation were altered in aged murine T-lymphocytes. Both calcium mobilization and tyrosine phosphorylation of phospholipase C gamma 1 (PLC gamma 1) were decreased in T-lymphocytes from old mice. In addition, there was less tyrosine phosphorylation of a 35/36 kDa protein both in whole cell lysates and in PLC gamma 1 immunoprecipitates from old mice. This 35/36 kDa phosphoprotein binds specifically to the SH2 domains of PLC gamma 1. Using a fusion protein containing the SH2 domains of PLC gamma 1 and human IgG1 heavy chain, we identified three additional proteins that bind to the SH2 domains which were tyrosine phosphorylated following CD3 x CD4 ligation to a lesser degree with age. The tyrosine phosphorylation of two phosphoproteins binding to a fusion protein consisting of the SH2 domains of GAP (ras GTPase-activating protein) and human IgG1 heavy chain was also reduced with aging. The observed binding to SH2 domains was thiol redox sensitive. Thus, decreases in antioxidants with age may be responsible for inhibitory effects on PLC gamma 1-phosphatidylinositol signaling through redox regulation of tyrosine phosphoproteins.
Grossmann
A
A
Department of Comparative Medicine, University of Washington, Seattle, USA.
Rabinovitch
P S
PS
Kavanagh
T J
TJ
Jinneman
J C
JC
Gilliland
L K
LK
Ledbetter
J A
JA
Kanner
S B
SB
D000375:Aging / Q000378:metabolism*; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003432:Cross-Linking Reagents; D007527:Isoenzymes / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D017252:CD3 Complex; D015704:CD4 Antigens; D003432:Cross-Linking Reagents; D007527:Isoenzymes; D010750:Phosphoproteins; D014443:Tyrosine; D010770:Phosphotransferases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium