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UCS15A, a non-kinase inhibitor of Src signal transduction

Oncogene volume 20, pages 2068–2079 (2001)Cite this article

Abstract

Src tyrosine kinase plays key roles in signal transduction following growth factor stimulation and integrin-mediated cell-substrate adhesion. Since src-signal transduction defects are implicated in a multitude of human diseases, we have sought to develop new ways to identify small molecule inhibitors using a yeast-based, activated-src over-expression system. In the present study, we describe the identification of a unique src-signal transduction inhibitor, UCS15A. UCS15A was found to inhibit the src specific tyrosine phosphorylation of numerous proteins in v-src-transformed cells. Two of these phosphoproteins were identified as bona-fide src substrates, cortactin and Sam68. UCS15A differed from conventional src-inhibitors in that it did not inhibit the tyrosine kinase activity of src. In addition, UCS15A appeared to differ from src-destabilizing agents such as herbimycin and radicicol that destabilize src by interfering with Hsp90. Our studies suggest that UCS15A exerted its src-inhibitory effects by a novel mechanism that involved disruption of protein-protein interactions mediated by src. One of the biological consequences of src-inhibition by UCS15A was its ability to inhibit the bone resorption activity of osteoclasts in vitro. These data suggest that UCS15A may inhibit the bone resorption activity of osteoclasts, not by inhibiting src tyrosine kinase activity, but by disrupting the interaction of proteins associated with src, thereby modulating downstream events in the src signal transduction pathway.

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Acknowledgements

We thank Dr Margaret Quinlan for the critical reading of this manuscript and for her helpful discussion. The technical assistance of Miss H Tsunoda is gratefully acknowledged.

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Authors and Affiliations

  1. Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., 3-6-6 Asahi-cho, Machida-shi, Tokyo, 194, Japan

    Sreenath V Sharma, Chitose Oneyama, Hirofumi Nakano & Masako Hamada

  2. Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411, Japan

    Yoshinori Yamashita, Nobuo Kosaka & Tatsuya Tamaoki

  3. Division of Morphogenesis, Okazaki National Research Institute, National Institute for Basic Biology, Nishigonaka 38, Myodaji, Okazaki 444-8585 Aichi, Japan

    Katsura Sugawara

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  1. Sreenath V Sharma
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Sharma, S., Oneyama, C., Yamashita, Y. et al. UCS15A, a non-kinase inhibitor of Src signal transduction. Oncogene 20, 2068–2079 (2001). https://doi.org/10.1038/sj.onc.1204296

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