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Signaling and Regulation

Bone Morphogenetic Protein-2–Induced Transformation Involves the Activation of Mammalian Target of Rapamycin

¹ Department of Surgery, Division of Thoracic Surgery, and ² Department of Surgery, Division of Surgical Sciences, University of Medicine and Dentistry, New Jersey Robert Wood Johnson Medical School, New Brunswick, New Jersey

Requests for reprints: John Langenfeld, Department of Surgery, Division of Thoracic Surgery, University of Medicine and Dentistry, New Jersey Robert Wood Johnson Medical School, MEB 536, One Robert Wood Johnson Place, P.O. Box 19, New Brunswick, NJ 08903-0019. Phone: 732-235-7802; Fax: 732-235-8150. E-mail: langenje{at}umdnj.edu

Bone morphogenetic protein-2 (BMP-2) is an evolutionary conserved protein that is essential for embryonic development. BMP-2 is highly expressed in 98% of human lung carcinomas with little expression in normal lung tissues. BMP-2 has been shown to enhance mobility, invasiveness, and metastasis of cancer cell lines. During development, BMP-2 induces the proto-oncogene phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway to regulate stem cell differentiation. We show that BMP-2 induces the phosphorylation of mTOR in A549 and H1299 lung cancer cell lines, which is attenuated by the PI3K antagonists LY-294002 and wortmannin. p70S6 kinase, which is a direct downstream target of mTOR, is also regulated by BMP-2 in lung cancer cell lines. We find that BMP-2 induces cyclin E in A549 and H1299 cells, which is mediated by the PI3K/mTOR signaling pathway. The regulation of cyclin E by BMP-2 occurs through a Smad 1/5–independent mechanism. Forced expression of BMP-2 in A549 cells (A549/BMP-2) induces transformation as shown by an increase in foci formation. The mTOR antagonist, rapamycin, prevented foci formation of the A549/BMP-2 cells. This study provides evidence that BMP-2-mediated transformation of lung cancer cells involves the activation of the PI3K/mTOR signaling pathway. (Mol Cancer Res 2005;3(12):679–84)

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