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*
Department of Pathology, University of Western Australia, Queen Elizabeth II Medical Center, Nedlands, Western Australia, Australia;
Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia
Recent studies indicate that c-Cbl and its oncogenic variants can
modulate the activity of protein tyrosine kinases. This finding is
supported by studies showing that c-Cbl interacts directly with a
negative regulatory tyrosine in ZAP-70, and that the levels of
tyrosine-phosphorylated ZAP-70 and numerous other proteins are
increased in TCR-stimulated thymocytes from c-Cbl-deficient mice. Here,
we demonstrate that this enhanced phosphorylation of ZAP-70 and that of
two substrates, LAT and SLP-76, is not due to altered protein levels
but is the consequence of two separate events. First, we find increased
expression of tyrosine-phosphorylated TCR
chain in c-Cbl-deficient
thymocytes, which results in a higher level of -chain-associated
ZAP-70 that is initially accessible for activation. Thus, more ZAP-70
is activated and more of its substrates (LAT and SLP-76) become
tyrosine-phosphorylated after TCR stimulation. However, an additional
mechanism of ZAP-70 regulation is evident at a later time
poststimulation. At this time, ZAP-70 from both normal and
c-Cbl-/- thymocytes becomes hyperphosphorylated; however,
only in normal thymocytes does this correlate with ZAP-70
down-regulation and a diminished ability to phosphorylate LAT and
SLP-76. In contrast, c-Cbl-deficient thymocytes display altered
phosphorylation kinetics, for which LAT phosphorylation is increased
and SLP-76 phosphorylation is sustained. Thus, the ability to
down-regulate the phosphorylation of two ZAP-70 substrates is impaired
in c-Cbl-/- thymocytes. These findings provide evidence
that c-Cbl is involved in the negative regulation of the
phosphorylation of LAT and SLP-76 by ZAP-70.
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