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Volume 270, Number 12, Issue of March 24, 1995 pp. 6872-6880
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Mouse Mammary Tumors Express Elevated Levels of RNA Encoding the Murine Homolog of SKY, a Putative Receptor Tyrosine Kinase (*)

(Received for publication, October 28, 1994)

Ian C. A. Taylor (1),  (2), (§), (¶),  Sophie Roy (1),  (2), (¶), (**),  Paul Yaswen (3), (§§),  Martha R. Stampfer (3), (§§),  Harold E. Varmus (1) (2)(¶¶)

From the  (1)Department of Microbiology and Immunology, University of California, San Francisco, California 94143, (2)NCI, National Institutes of Health, Bethesda, Maryland 20892, and the (3)Lawrence Berkeley Laboratory, University of California, Berkeley, California 94720

ABSTRACT

To gain insight into the signal transduction pathways utilized by the Wnt-1-responsive mammary epithelial cell line C57MG, we screened for non-src family member tyrosine kinases expressed in these cells using a polymerase chain reaction-based technique. We identified five cDNA clones encoding receptor tyrosine kinases for which the ligand is known (fibroblast growth factor receptor, platelet-derived growth factor receptor, epithelial growth factor receptor, insulin receptor, and insulin-like growth factor receptor), two putative receptor tyrosine kinases for which the ligand remains to be identified (the products of ryk and the mouse klg homolog), and a novel tyrosine kinase. We cloned cDNAs encoding both the murine and human homologs of this kinase, the sequences of which were subsequently published under the names sky (Ohashi, K., Mizuno, K., Kuma, K., Miyata, T., and Nakamura, T.(1994) Oncogene 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, 10720-10728). Mouse sky RNA levels are abundant in mammary tumors derived from transgenic mice that express wnt-1, fgf-3, or both oncogenes in their mammary 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 of sky is expressed at elevated levels when normal human mammary epithelial cells are rendered tumorigenic by the introduction of two viral oncogenes. Transient transfection of the human SKY cDNA into the quail fibrosarcoma cell line QT6 reveals that SKY is an active tyrosine kinase that augments the level of cellular phosphotyrosine. Introduction of murine Sky into RatB1a fibroblasts by retrovirus-mediated gene transfer 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 progression of mammary tumors.

FOOTNOTES

*
This work was supported by National Institutes of Health Grant CA-39832. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§
A Damon Runyan-Walter Winchell Cancer Research Fund Fellow.

Contributed equally to this work.

**
Supported by a Centennial Fellowship from the Medical Research Council of Canada.

§§
Received support from National Institutes of Health Grants CA-54247 and CA-24844 as well as from the Office of Energy Research, Office of Health and Environmental Research, U. S. Dept. of Energy under Contract DE-AC0376SF00098.

¶¶
Formerly an American Cancer Society Research Professor. To whom correspondence should be addressed: NCI, National Institutes of Health, Bldg. 49, Rm. 4A56, 9000 Rockville Pike, Bethesda, MD 20892. Tel.: 301-496-0429; Fax: 301-496-0332.

(^1)
The abbreviations used are: PTKs, protein tyrosine kinases; PCR, polymerase chain reaction; HA, hemagglutinin; FBS, fetal bovine serum; MEF, mouse embryo fibroblasts; HMEC, human mammary epithelial cells; DME media, Dulbecco's minimal essential media; bp, base pair(s); kb, kilobase(s); MOPS, 4-morpholinepropanesulfonic acid; PAGE, polyacrylamide gel electrophoresis; BSA, bovine serum albumin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

ACKNOWLEDGEMENTS

We thank Lucy Godley, Linda Yuschenkoff, and Helen Kwan for assistance in dissecting mouse organs and mammary tumors; Ken Kaplan for primary, immortalized, and oncogene-transformed mouse embryo fibroblast cells; Martin Scott and David Baltimore for 293T cells; Daniel Afar and Owen Witte for retroviral vectors; Caroline Alexander and John Ashkenas for the beta-casein probe; Don Ganem for support; Don Macrae for computer advice; Steve Chuck for helpful comments on the manuscript; and the surviving members of the Varmus lab at UCSF for many useful discussions.

Note Added in Proof-Lai et al. (Lai, C., Gore, M., and Lemke, G.(1994) Oncogene9, 2567-2578) recently have reported the cloning and characterization of tyro3, which is identical to sky.

©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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