Endoglin Regulates Prostate Cancer Invasion through Activin and Bone Morphogenetic Protein Type II Receptors and Interfaces with Beta3 Integrin and Focal Adhesions

Prostate cancer (PCa) is the most common cancer of American men. Essentially all mortality from PCa is due to the development of metastatic disease. Understanding how that process is regulated is therefore critical. We previously demonstrated that endoglin, a type III transforming growth factor β (TGF-β) superfamily receptor, suppresses human PCa cell invasion and metastasis. Endoglin-mediated suppression of invasion (EMSI) occurs through activation of a TGF-β signaling involving the type I TGF-β receptor, activin receptor-like kinase 2 (ALK2) and the downstream effector Smad1. This study addressed the related questions of what are the remaining components of a canonical TGF-β signaling complex required for EMSI and whether endoglin interacts with integrins, a transmembrane receptor that mediates adhesion and signaling.;In this study we demonstrate for the first time that two type II TGF-β receptors are required for endoglin-mediated suppression of invasion: activin A receptor type IIA (ActRIIA) and bone morphogenetic protein receptor type II (BMPRII). Downstream signaling through these receptors is predominantly mediated by Smad1. ActRIIA stimulates Smad1 activation in a kinase-dependent manner, and this is required for suppression of invasion. The contributions of BMPRII are more complex. BMPRII inhibits Smad1 signaling dependent on its tail domain and level of expression. It promotes EMSI independent of this effect. We identify and characterize a novel interaction between ActRIIA and BMPRII and between endoglin and β3 integrin. Finally we demonstrate regulation of focal adhesions by endoglin.;From this data, we propose a model in which a PCa cells regulate invasion through a TGF-β receptor complex containing endoglin, ActRIIA, and ALK2 signaling through Smad1, while BMPRII provides distinct, simultaneously required context. We further suggest that interaction between endoglin and β3 integrin represents a key point of interaction that integrates multiple known pathways that regulate cancer invasion. The data presented herein refine our knowledge of mechanisms that regulate the invasive potential of prostate cancer cells and suggest additional avenues for future research.