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J Biol Chem, Vol. 273, Issue 50, 33856-33863, December 11, 1998
in Vivo
From the Department of Medicine, Yale Medical School,
New Haven, Connecticut 06520
The CD45 protein tyrosine phosphatase (PTPase)
has been shown to regulate the activity of Lck and Fyn protein tyrosine
kinases in T cells. However, it is not clear that these constitute the only CD45 substrates. Moreover, the manner by which PTPase activity and
substrate recruitment are regulated, is poorly understood. Previous
in vitro studies suggest that the first cytoplasmic PTPase domain (D1) of CD45 is the active PTPase, which may be regulated by an
enzymatically inactive second PTPase domain (D2). However, the function
of CD45 D2 in vivo is unknown. In this study,
reconstitution of CD45
T cells with specific CD45 PTPase
mutants allowed demonstration of a critical role for D2 in TCR-mediated
interleukin (IL)-2 production. Specifically, replacement of CD45 D2
with that of the LAR PTPase to form a CD45/LAR:D2 chimera, abrogates
CD45-dependent IL-2 production. This effect cannot be
accounted for by loss of PTPase activity per se. The
expression of D1 substrate-trapping mutants reveals an in
vivo interaction between CD45 and TCR-
that is dependent on
CD45 D2. Thus, cells expressing CD45 lacking D2 exhibit abnormal TCR-mediated signaling characterized by hyperphosphorylation of and
deficient ZAP-70 phosphorylation. These data suggest an essential role
for CD45 D2 in TCR-regulated IL-2 production through substrate
recruitment of the chain.
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