Abstract 491: Endoglin suppresses prostate cancer invasion through two distinct type II TGF-β receptors

Prostate cancer (PCa) is the most common cancer of American men and the second leading cause of cancer-related death. Death from PCa results from the development of metastatic disease, yet the processes underlying progression from localized to invasive and ultimately metastatic disease remain poorly understood. Our group has previously shown that endoglin, an auxiliary TGF-β superfamily receptor, is lost with PCa progression. Restoration of endoglin expression inhibits PCa cell migration, invasion, and metastasis in pre-clinical models. Endoglin-mediated suppression of PCa invasion (EMSI) is mediated through the type I TGF-β receptor ALK2 and the downstream effector Smad1. Given that TGF-β signaling minimally requires both a type I and a type II TGF-β receptor (RII), we sought to determine the RII(s) involved in EMSI. We now show that silencing of either the type IIA activin receptor (ActRII) or the type II bone morphogenic protein receptor (BMPRII) abrogates endoglin's invasion suppressive effects. Surprisingly, ActRII and BMPR2 have opposite effects on downstream Smad1 signaling: ActRII promotes basal and endoglin-mediated Smad1 transcriptional activity dependent on its kinase domain, while BMPR2 suppresses Smad1 transcriptional activity independent of its kinase domain but dependent on its cytoplasmic tail. Moreover, we show that engagement of distinct BMP-responsive R-Smads (i.e. Smad1, Smad5, & Smad8) does not account for differential signaling and confirm that Smad1 is the main mediator downstream of endoglin. We posit the existence of two parallel pathways that are required for EMSI: an ActRII / ALK2 / Smad1 pathway and a second, as-yet-uncharacterized pathway involving BMPR2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 491. doi:1538-7445.AM2012-491