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Cancer-Associated Transforming Growth Factor β Type II Receptor Gene Mutant Causes Activation of Bone Morphogenic Protein-Smads and Invasive Phenotype

Departments of ¹ Internal Medicine and ² Molecular Genetics, Microbiology and Immunology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and The Cancer Institute of New Jersey, New Brunswick, New Jersey and ³ Oncology Division, Lilly Research Labs, Eli Lilly and Co., Indianapolis, Indiana

Requests for reprints: Michael Reiss, Division of Medical Oncology, Department of Internal Medicine, and Department of Molecular Genetics, Microbiology and Immunology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and The Cancer Institute of New Jersey, Room 2007, 195 Little Albany Street, New Brunswick, NJ 08903. Phone: 732-235-6031; Fax: 815-333-3972; E-mail: michael.reiss{at}umdnj.edu.

Key Words: TGFβ • receptor • mutation • signaling • Smad • activation • response • BMP

Transforming growth factor β (TGFβ) plays a key role in maintaining tissue homeostasis by inducing cell cycle arrest, differentiation and apoptosis, and ensuring genomic integrity. Furthermore, TGFβ orchestrates the response to tissue injury and mediates repair by inducing epithelial to mesenchymal transition and by stimulating cell motility and invasiveness. Although loss of the homeostatic activity of TGFβ occurs early on in tumor development, many advanced cancers have coopted the tissue repair function to enhance their metastatic phenotype. How these two functions of TGFβ become uncoupled during cancer development remains poorly understood. Here, we show that, in human keratinocytes, TGFβ induces phosphorylation of Smad2 and Smad3 as well as Smad1 and Smad5 and that both pathways are dependent on the kinase activities of the type I and II TGFβ receptors (TβR). Moreover, cancer-associated missense mutations of the TβRII gene (TGFBR2) are associated with at least two different phenotypes. One type of mutant (TGFBR2^E526Q) is associated with loss of kinase activity and all signaling functions. In contrast, a second mutant (TGFBR2^R537P) is associated with high intrinsic kinase activity, loss of Smad2/3 activation, and constitutive activation of Smad1/5. Furthermore, this TGFBR2 mutant endows the carcinoma cells with a highly motile and invasive fibroblastoid phenotype. This activated phenotype is TβRI (Alk-5) independent and can be reversed by the action of a dual TβRI and TβRII kinase inhibitor. Thus, identification of such activated TβRII receptor mutations in tumors may have direct implications for appropriately targeting these cancers with selective therapeutic agents. [Cancer Res 2008;68(6):1656–66]