MOUSE MAMMARY-TUMORS EXPRESS ELEVATED LEVELS OF RNA-ENCODING THE MURINE HOMOLOG OF SKY, A PUTATIVE RECEPTOR TYROSINE KINASE

To gain insight into the signal transduction pathways utilized by the Wnt-1-responsive mammary epithelial cell line C57MG, we screened for n on-src family member tyrosine kinases expressed in these cells using a polymerase chain reaction-based technique. We identified five cDNA cl ones encoding receptor tyrosine kinases for which the ligand is known (fibroblast growth factor receptor, platelet-derived growth factor rec eptor, epithelial growth factor receptor, insulin receptor, and insuli n-like growth factor receptor), two putative receptor tyrosine kinases for which the ligand remains to be identified (the products of ryk an d the mouse klg homolog), and a novel tyrosine kinase. We cloned cDNAs encoding both the murine and human homologs of this kinase, the seque nces of which were subsequently published under the names sky (Ohashi, K., Mizuno, K., Kuma, K., Miyata, T., and Nakamura, T. (1994) Oncogen e 9, 699-705) and rse (Mark, M. R., Scadden, D. T., Wang, Z., Gu, Q., Goddard, A., and Godowski, P. J. (1994) J. Biol. Chem. 269, 10720-1072 8). Mouse sky RNA levels are abundant in mammary tumors derived from t ransgenic mice that express wnt-1, fgf-3, or both oncogenes in their m ammary glands. However, little or no expression of sky is detected in mammary glands from virgin animals or in preneoplastic mammary glands from wnt-1 transgenic mice. Moreover, we find that the human homolog o f sky is expressed at elevated levels when normal human mammary epithe lial cells are rendered tumorigenic by the introduction of two viral o ncogenes. Transient transfection of the human SKY cDNA into the quail fibrosarcoma cell line QT6 reveals that SKY is an active tyrosine kina se that augments the level of cellular phosphotyrosine. Introduction o f murine Sky into RatB1a fibroblasts by retrovirus-mediated gene trans fer results in morphological transformation, growth in soft agar, and the formation of tumors in nude mice. These data raise the possibility that the Sky tyrosine kinase is involved in the development and/or pr ogression of mammary tumors.