International Immunology, Vol 9, 291-306, Copyright © 1997 by Oxford University Press
K Lin and KM Abraham
Previous studies suggest that p56(lck) activity influences thymocyte
development at a stage prior to TCR alphabeta expression. Transgenic mice
that express high levels of p56(lck) activity during thymopoiesis develop
thymic lymphomas consisting of cells with immature surface phenotypes. We
have utilized cell lines derived from lck-induced thymic tumors to define
biochemical pathways regulated by p56(lck) activity in immature thymocytes.
Here we report that components of the Ras/Raf/MAPK pathway are
constitutively activated in these lck-transformed immature thymoblasts.
p56(lck) utilizes Shc and Grb2 adaptors to mediate activation of p21(ras)
in the thymoblast lines by promoting tyrosine phosphorylation of the Shc
protein and constitutive interaction between Shc and Grb2. The putative
guanine nucleotide exchange factor p95(vav) is also maintained in
constitutively tyrosine phosphorylated form as a result of elevated Lck
activity. One target of activated Ras, the Raf-1 kinase, is
hyperphosphorylated and downstream targets of activated Raf- 1, Erk1 and
Erk2, are hyperphosphorylated and activated in Lck- transformed thymocytes.
Forskolin treatment reverses Raf-1 hyperphosphorylation in the cells and
inhibits proliferation by blocking G1/S transition. In contrast,
conventional protein tyrosine kinase inhibitors block proliferation by
arresting Lck thymoblasts at G2/M. Lck-mediated stimulation of the
Ras/Raf/MAPK pathway is also required to maintain cell viability by
preventing programmed cell death. In summary, p56(lck) activity stimulates
G1/S transition in immature thymoblasts and maintains cell viability via
transduction of constitutive activation signals downstream to components of
the Ras/Raf/MAPK pathway.
ARTICLES
Targets of p56(lck) activity in immature thymoblasts: stimulation of the Ras/Raf/MAPK pathway
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore 21201, USA.
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