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

Transforming growth factor B (TGFB) plays a key role in maintaining tissue homeostasis by inducing cell cycle arrest, differentiation and apoptosis, and ensuring genomic integrity. Furthermore, TGFB 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 TGFB 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 TGFB become uncoupled during cancer development remains poorly understood. Here, we show that, in human keratinocytes, TGFB 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 TGFB receptors (TBR). Moreover, cancer-associated missense mutations of the TBRII gene (TGFBR2) are associated with at least two different phenotypes. One type of mutant (TGFBR2) is associated with loss of kinase activity and all signaling functions. In contrast, a second mutant (TGFBR2) 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 TBRI (Alk-5) independent and can be reversed by the action of a dual TBRI and TBRII kinase inhibitor. Thus, identification of such activated TBRII receptor mutations in tumors may have direct implications for appropriately targeting these cancers with selective therapeutic agents. [Cancer Res 2008;68(6):1656–66]