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J Biol Chem, Vol. 275, Issue 9, 6411-6416, March 3, 2000
From the Laboratory of Cell Signaling, NHLBI, National Institutes
of Health, Bethesda, Maryland 20892
Upon stimulation of cells with platelet-derived
growth factor (PDGF), phospholipase C-
Differential Roles of the Src Homology 2 Domains of
Phospholipase C-
1 (PLC-1) in Platelet-derived Growth
Factor-induced Activation of PLC-1 in Intact Cells*
1 (PLC-1) binds to the
tyrosine-phosphorylated PDGF receptor through one or both of its Src
homology 2 (SH2) domains, is phosphorylated by the receptor kinase, and
is thereby activated to hydrolyze phosphatidylinositol
4,5-bisphosphate. Association of PLC-1 with the insoluble
subcellular fraction is also enhanced in PDGF-stimulated cells. The
individual roles of the two SH2 domains of PLC-1 in mediating the
interaction between the enzyme and the PDGF receptor have now been
investigated by functionally disabling each domain. A critical Arg
residue in each SH2 domain was mutated to Ala. Both wild-type and
mutant PLC-1 proteins were transiently expressed in a
PLC-1-deficient fibroblast cell line, and these transfected cells
were stimulated with PDGF. The mutant protein in which the
COOH-terminal SH2 domain was disabled bound to the PDGF receptor.
Accordingly, it was phosphorylated by the receptor, catalyzed the
production of inositol phosphates, and mobilized intracellular calcium
to extents similar to (but slightly less than) those observed with the
wild-type enzyme. In contrast, the mutant in which the
NH2-terminal SH2 domain was impaired did not bind to
the PDGF receptor and consequently was neither phosphorylated nor
activated. These results suggest that the NH2-terminal SH2
domain, but not the COOH-terminal SH2 domain, of PLC-1 is required
for PDGF-induced activation of PLC-1. Functional impairment of the
SH2 domains did not affect the PDGF-induced redistribution of PLC-1,
suggesting that recruitment of PLC-1 to the particulate fraction
does not involve the SH2 domains.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Bldg. 3, Rm. 122, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-9646; Fax: 301-480-0357; E-mail: sgrhee@nih.gov.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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