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Vol. 11, Issue 5, 1585-1595, May 2000
Medical Research Council Laboratory for Molecular Cell Biology and
Department of Biochemistry, University College London, London, WC1E
6BT, United Kingdom
Tyrosine kinases of the Src family are synthesized as cytosolic
proteins that subsequently translocate to membranes. Little is known of
the mechanisms responsible for targeting these proteins to membranes,
although a role for the cytosolic chaperone Hsp90 has been proposed.
Here, we have studied the involvement of Hsp90 in the synthesis,
membrane binding, and maintenance of the Src-kinase Lck. Using specific
inhibitors of Hsp90, geldanamycin and radicicol, we found that
functional Hsp90 is essential for the stability of newly synthesized,
but not mature, Lck. Similar results were obtained for two other
Src-kinases, c-Src and Lyn. In contrast, LckY505F and Lck
SH2,
constitutively active Lck mutants lacking the C-terminal regulatory
tyrosine or the entire Src homology 2 domain, respectively,
required Hsp90 activity to stabilize the mature proteins. Lck
synthesized in the absence of Hsp90 activity was degraded within 30-45
min. This unstable Lck was myristoylated normally but did not associate
with membranes or CD4, interactions that normally start within minutes
of the completion of Lck synthesis. A construct composed of the
N-terminal unique domain of Lck fused to green fluorescent protein did
not require Hsp90 activity during synthesis. In addition, this protein
associated with membranes efficiently in the absence of Hsp90 activity.
Together these data suggest that interaction with Hsp90 is necessary
for the correct synthesis and subsequent membrane binding of Lck.
However, Hsp90 does not appear to play a direct role in Lck membrane,
or CD4, association.
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