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J. Biol. Chem., Vol. 277, Issue 32, 29330-29341, August 9, 2002
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From the Center for Cardiovascular Research, University of
Rochester, Rochester, New York 14642, the § Department
of Oral Surgery, Yokohama City University, Yokohama, Japan
236-0004, and the ¶ Department of Pharmacology,
Tokushima University, Tokushima, Japan 770-8503
SHP-2, a nontransmembrane-type protein-tyrosine
phosphatase that contains two Src homology 2 (SH2) domains, is thought
to participate in growth factor signal transduction pathways via SH2
domain interactions. To determine the role of each region of SHP-2 in
platelet-derived growth factor signaling assayed by Elk-1 activation,
we generated six deletion mutants of SHP-2. The large SH2 domain
deletion SHP-2 mutant composed of amino acids 198-593
(SHP-2-(198-593)), but not the smaller SHP-2-(399-593), showed
significantly higher SHP-2 phosphatase activity in vitro. In contrast, SHP-2-(198-593) mutant inhibited wild type SHP-2 phosphatase activity, whereas SHP-2-(399-593) mutant increased activity. To understand these functional changes, we focused on the
docking protein Gab1 that assembles signaling complexes. Pull-down experiments with Gab1 suggested that the C-terminal region of SHP-2 as
well as the SH2 domains (N-terminal region) associated with Gab1, but
the SHP-2-(198-593) mutant did not associate with Gab1. SHP-2-(1-202)
or SHP-2-(198-593) inhibited platelet-derived growth factorinduced
Elk-1 activation, but SHP-2-(399-593) increased Elk-1 activation.
Co-expression of SHP-2-(1-202) with SHP-2-(399-593) inhibited
SHP-2-(399-593)/Gab1 interaction, and the SHP-2-(399-593) mutant
induced SHP-2 phosphatase and Elk-1 activation, supporting the
autoinhibitory effect of SH2 domains on the C-terminal region of SHP-2.
These data suggest that both SHP-2/Gab1 interaction in the C-terminal
region of SHP-2 and increased SHP-2 phosphatase activity are important
for Elk-1 activation. Furthermore, we identified a novel sequence for
SHP-2/Gab1 interactions in the C-terminal region of SHP-2.
The Novel Role of the C-terminal Region of SHP-2
INVOLVEMENT OF Gab1 AND SHP-2 PHOSPHATASE ACTIVITY IN Elk-1
ACTIVATION*
,,
*
This work was supported by National Institutes of Health
Grants HL61319 (to J. A.) and HL44721 and HL49192 (to B. C. B.).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.
These three authors contributed equally to this work.
To whom correspondence should be addressed: Cardiology Unit,
Box 679, 601 Elmwood Ave., University of Rochester School of Medicine
and Dentistry, Rochester, NY 14642. Tel.: 716-273-1686; Fax:
716-275-9895; E-mail: jun-chi_abe@urmc.rochester.edu.
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