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Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
To study the mechanism by which protein tyrosine phosphatases
(PTPs) regulate CD3-induced tyrosine phosphorylation, we investigated
the distribution of PTPs in subdomains of plasma membrane. We report
here that the bulk PTP activity associated with T cell membrane is
present outside the lipid rafts, as determined by sucrose density
gradient sedimentation. In Jurkat T cells, 
5–10% of Src homology 2
domain-containing tyrosine phosphatase (SHP-1) is constitutively
associated with plasma membrane, and nearly 50% of SHP-2 is
translocated to plasma membrane after vanadate treatment. Similar to
transmembrane PTP, CD45, the membrane-associated populations of SHP-1
and SHP-2 are essentially excluded from lipid rafts, where other
signaling molecules such as Lck, linker for activation of T cells, and
CD3
are enriched. We further demonstrated that CD3-induced tyrosine
phosphorylation of these substrates is largely restricted to lipid
rafts, unless PTPs are inhibited. It suggests that a restricted
partition of PTPs among membrane subdomains may regulate protein
tyrosine phosphorylation in T cell membrane. To test this hypothesis,
we targeted SHP-1 into lipid rafts by using the N-terminal region of
Lck (residues 1–14). The results indicate that the expression of
Lck/SHP-1 chimera inside lipid rafts profoundly inhibits CD3-induced
tyrosine phosphorylation of CD3/
, IL-2 generation, and nuclear
mobilization of NF-AT. Collectively, these results suggest that the
exclusion of PTPs from lipid rafts may be a mechanism that potentiates
TCR/CD3 activation.
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