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The Ras GTPase-activating protein (GAP) is a target for protein
tyrosine kinases of both the receptor and cytoplasmic classes and may
serve to integrate tyrosine kinase and Ras signaling pathways. In this
report, we provide evidence that GAP is an SH3 domain-binding protein
and substrate for the Src-related tyrosine kinase Hck, which has been
implicated in the regulation of myeloid cell growth, differentiation,
and function. Wild-type (WT) or kinase-inactive (K269E) mutant Hck
proteins were co-expressed with bovine GAP using the baculovirus/Sf-9
cell system. GAP was readily phosphorylated on tyrosine by WT but not
K269E Hck. GAP was present in WT Hck immunoprecipitates from the
co-infected cells, indicative of Hck
Volume 270,
Number 24,
Issue of June 16, pp. 14718-14724, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
GAP complex formation.
Unexpectedly, GAP also associated with the kinase-inactive mutant of
Hck, suggesting that tyrosine autophosphorylation of Hck is not
required for complex formation. The WT and K269E forms of Hck also
associated with GAP mutants lacking either the C-terminal catalytic
domain (
CAT) or the Src homology region (SH), indicating that
these GAP domains are dispensable for complex formation. Recombinant
GST fusion proteins containing the Hck, Src, Fyn, or Lck SH3 domains
associated with full-length GAP, CAT, and SH, all of which
share an N-terminal proline-rich region resembling an SH3-binding motif
(PPLPPPPPQLP). Deletion of the highly conserved YXY sequence
from the Hck SH3 domain abolished binding. GAP-SH3 interaction was also
inhibited by the proline-rich peptide GFPPLPPPPPQLPTLG, which
corresponds to N-terminal amino acids 129-144 of bovine GAP. An
N-terminal deletion mutant of GAP lacking this proline-rich region did
not bind to the Hck SH3 domain. These data implicate the Hck SH3 domain
in GAP interaction, and suggest a general function for the SH3 domains
of Src family kinases in recognition of GAP via its proline-rich
N-terminal domain.
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