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Volume 271, Number 48, Issue of November 29, 1996 pp. 30956-30963
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Brk, a Breast Tumor-derived Non-receptor Protein-tyrosine Kinase, Sensitizes Mammary Epithelial Cells to Epidermal Growth Factor

(Received for publication, February 5, 1996, and in revised form, September 3, 1996)

Tahereh Kamalati , Helen E. Jolin , Philip J. Mitchell , Karen T. Barker , Laura E. Jackson ^¶ , Christopher J. Dean ^¶ , Martin J. Page , Barry A. Gusterson and Mark R. Crompton

From the  Section of Cell Biology and Experimental Pathology and ^¶ Section of Immunology, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG and  GlaxoWellcome Research Laboratories, Gunnels Wood Road, Stevenage, Herts. SG1 2NY, United Kingdom

brk (breast tumor kinase) shows homology to the src family of non-receptor protein-tyrosine kinases and is expressed in breast carcinomas. In order to investigate the role of brk in breast tumor development, we have examined the growth and transformation properties of human mammary epithelial cells engineered to overexpress Brk. Interestingly, like c-Src, overexpression of Brk leads to sensitization to EGF, and also results in a partially transformed phenotype. Further investigation of the latter activity was attempted by mutational analysis, targeting key residues known to affect tyrosine kinase activity in Src-like kinases. Mutation of amino acid residue Lys-219 to Met, by analogy to Src, abolished both kinase activity and transformation capacity. Mutation of amino acid residue Tyr-447 to Phe, however, resulted in a decrease in transforming potential without affecting kinase activity. These results suggest that while Src and Brk share some functional properties, they act differently during transformation. These differences are discussed in the context of the mechanisms underlying breast cancer development.

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