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J. Biol. Chem., Vol. 277, Issue 39, 36465-36470, September 27, 2002
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From the Our previous studies demonstrated that Csk
homologous kinase (CHK) acts as a negative growth regulator of human
breast cancer through inhibition of ErbB-2/neu-mediated Src family
kinase activity (Bougeret, C., Jiang, S., Keydar, I., and Avraham, H. (2001) J. Biol. Chem. 276, 33711-33720. The interaction
between the CHK SH2 domain and Tyr(P)1248 of
the ErbB-2 receptor has been shown to be specific and critical for CHK
function. In this report, we investigated whether the interaction of
the CHK SH2 domain and ErbB-2 is directly related to the inhibition of
heregulin-stimulated Src kinase activity. We constructed three
CHK SH2 domain binding mutants: G129R (enhanced binding), R147K
(inhibited binding), and R147A (disrupted binding). NMR spectra for the
domains of each construct were used to evaluate their interaction with
a Tyr(P)1248-containing ErbB-2 peptide. G129R showed
enhanced binding to ErbB-2, whereas binding was completely disrupted by
R147A. The enhanced binding mutant showed chemical shift changes at the
same residues as wild-type CHK, indicating that this mutant has the
same binding characteristics as the wild-type protein. Furthermore,
inhibition of heregulin-stimulated Src kinase activity was markedly
diminished by R147A, whereas G129R-mediated inhibition was stronger as
compared with wild-type CHK. These results indicate that the specific
interaction of CHK and ErbB-2 via the SH2 domain of CHK is directly
related to the growth inhibitory effects of CHK. These new CHK high
affinity binding constructs may serve as good candidates for inhibition of the ErbB-2/Src transduction pathway in gene therapy studies in
breast cancer.
This paper is dedicated to Charlene Engelhard for her continuing
friendship and support of our research program.
Csk Homologous Kinase (CHK) and ErbB-2 Interactions Are
Directly Coupled with CHK Negative Growth Regulatory Function in
Breast Cancer*
,§,,, and
Division of Experimental Medicine,
Beth Israel Deaconess Medical Center, Harvard Medical School,
Boston, Massachusetts 02115 and the ¶ Department of Biochemistry,
Tufts University School of Medicine, Boston, Massachusetts 02111
*
This work was supported in part by National Institutes of
Health Grants CA 76226 and CA 87290 (to H. A.), United States Army Medical Research and Material Command Grants DAMD 17-98-1-8032 and DAMD
17-99-1-9078 (to H. A.), Experienced Breast Cancer Research Grant
34080057089 (to H. A.), the Milheim Foundation (to H. A.), the
Massachusetts Department of Public Health (to H. A.), and the American
Cancer Society (to J. D. 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.
To whom correspondence should be addressed: Div. of
Experimental Medicine, Beth Israel Deaconess Medical Center,
Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA
02115. Tel.: 617-667-0073; Fax: 617-975-6373; E-mail:
havraham@caregroup.harvard.edu.
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