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J. Biol. Chem., Vol. 276, Issue 36, 33711-33720, September 7, 2001
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From the In this report, we analyzed the
expression and kinase activities of Csk and CHK kinases in normal
breast tissues and breast tumors and their involvement in HRG-mediated
signaling in breast cancer cells. Csk expression and kinase activity
were abundant in normal human breast tissues, breast carcinomas, and
breast cancer cell lines, whereas CHK expression was negative in normal breast tissues and low in some breast tumors and in the MCF-7 breast
cancer cell line. CHK kinase activity was not detected in human breast
carcinoma tissues (12 of 12) or in the MCF-7 breast cancer cell line
(due to the low level of CHK protein expression), but was significantly
induced upon heregulin (HRG) stimulation. We have previously shown that
CHK associates with the ErbB-2/neu receptor upon HRG stimulation
via its SH2 domain and that it down-regulates the
ErbB-2/neu-activated Src kinases. Our new findings demonstrate that Csk
has no effect on ErbB-2/neu-activated Src kinases upon HRG treatment
and that its kinase activity is not modulated by HRG. CHK significantly
inhibited in vitro cell growth, transformation, and
invasion induced upon HRG stimulation. In addition, tumor growth of wt
CHK-transfected MCF-7 cells was significantly inhibited in nude mice.
Furthermore, CHK down-regulated c-Src and Lyn protein expression and
kinase activity, and the entry into mitosis was delayed in the wt
CHK-transfected MCF-7 cells upon HRG treatment. These results indicate
that CHK, but not Csk, is involved in HRG-mediated signaling pathways,
down-regulates ErbB-2/neu-activated Src kinases, and inhibits invasion
and transformation of breast cancer cells upon HRG stimulation. These
findings strongly suggest that CHK is a novel negative growth regulator
of HRG-mediated ErbB-2/neu and Src family kinase signaling pathways in
breast cancer cells.
This paper is dedicated to Charlene Engelhard for her continuing
friendship and support for our research program.
Functional Analysis of Csk and CHK Kinases in Breast Cancer
Cells*
,,¶
Division of Experimental Medicine, Beth
Israel Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts 02115 and the § Department of Cell Research
and Immunology, Tel Aviv University, Ramat Aviv 69978, Israel
*
This work was supported in part by National Institutes of
Health Grants CA 76226 and CA 87290 (to H. A.), by U.S. Army Medical Research and Material Command Grants DAMD 17-98-1-8032 and DAMD 17-99-1-9078 (to H. A.), by Experienced Breast Cancer Research Grant
34080057089 (to H. A.), by the Milheim Foundation (to H. A.), and by
the Massachusetts Department of Public Health (to H. A.) and (to
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.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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