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J. Biol. Chem., Vol. 278, Issue 34, 31574-31583, August 22, 2003
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From the
Departments of Otolaryngology,
Pharmacology, and
¶Molecular Genetics and Biochemistry, University
of Pittsburgh School of Medicine, and the
||University of Pittsburgh Cancer Institute,
Pittsburgh, Pennsylvania 15213 and and the **Abbott
Bioresearch Center, Worcester, Massachusetts 01605
Signal transducer and activator of transcription (STAT) proteins are
constitutively activated in many malignancies, including squamous cell
carcinoma of the head and neck (SCCHN). Previously, we reported that
phosphorylation of the epidermal growth factor receptor (EGFR) is linked to
activation of STATs 3 and 5 in SCCHN cells. The present study was undertaken
to determine the role of Src family kinases in STAT activation and SCCHN
growth. The Src family kinases c-Src, c-Yes, Fyn, and Lyn were expressed and
activated by transforming growth factor-
stimulation in all four SCCHN
cell lines examined but not in corresponding normal epithelial cells. In nine
SCCHN cell lines tested, Src phosphotyrosine expression levels were highly
correlated with activation levels of STATs 3 and 5. Co-immunoprecipitation
analysis demonstrated interaction between c-Src and STATs 3 or 5 and EGFR in
SCCHN cells, but no heterodimerization was detected between STAT3 and STAT5.
SCCHN cells treated with either of two Src-specific inhibitors or transfected
with a dominant-negative c-Src construct demonstrated decreased activation of
STATs 3 and 5 and reduced growth rates in vitro. These results
demonstrate a role for Src kinases in mediating activation of STATs 3 and 5 in
concert with the EGFR in SCCHN cells. Strategies to target Src activation may
contribute to the treatment of cancers that demonstrate increased levels of
EGFR and STATs, including SCCHN.
Received for publication, April 4, 2003 , and in revised form, May 17, 2003.
* This work was supported by National Institutes of Health Grant CA77308 (to J. R. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This 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: The Eye and Ear Institute, Suite
500, 200 Lothrop St., Pittsburgh, PA 15213. Tel.: 412-647-5280; Fax:
412-647-2080; E-mail:
jgrandis{at}pitt.edu.
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