Differential Regulation of Processing of Type I BMP Receptor Isoforms: Implications for Signaling in Ovarian Cancer

The transforming growth factor-β (TGF-β) superfamily of ligands includes bone morphogenic proteins (BMPs), and plays crucial roles in tumor development and metastasis. TGF-β superfamily signals also regulate the differentiation and proliferation of normal tissues, and are interpreted with dependence on cellular context. This duality of effects complicates the targeting of TGF-β superfamily receptors and ligands in therapeutic settings. Moreover, the processing, trafficking and function of TGF-β superfamily receptors also depend on cellular context, and changes to such context are induced by different chemotherapy drugs.

The type I BMP receptors (BMPRIa and BMPRIb) display extensive sequence similarity; however, their knockout in mouse models yield different outcomes, suggesting that they perform different functions. Our results show that the prevalent isoform of BMPR1b (isoform 1) differs from its alternatively spliced isoform 2 and from BMPRIa in the mode of its ER translocation. Moreover, we show that only BMPR1a is N-glycosylated and that receptor glycosylation is important for the folding and plasma membrane localization of type I BMP receptors. Together, these data raise the possibilities of differential regulation of the processing of BMPR1a and BMPR1b, and of their differential susceptibility to agents that alter the cellular context. We test these scenarios through the examination of the effects of 2-Deoxy-D-Glucose (2-DG), an anti-cancer therapy agent, in ES-2 mesenchymal-like human ovarian cancer cell model. Our data point to the importance of BMP signaling in the induction of the aggressive metastatic phenotype of ES-2 cells. We showed that 2-DG altered BMPRIa-dependent responses through perturbation of BMPRIa glycosylation. These findings point to the possibility of manipulating the amount, localization and function of TGF-β superfamily signals as a future therapeutic approach.