Activins are classified as members of the TGFbeta superfamily of signaling molecules and both activin and TGFbeta ligands signal through structurally and functionally related serine/threonine kinase receptors. Defects in these signaling pathways have been associated with the initiation and progression of the cancer phenotype. Inactivating mutations in the TGFbeta type II receptor gene, TGFbetaR2, have been identified in a variety of tumors and cell lines, particularly those with microsatellite instability (MSI). More recently, mutations in the activin type II receptor gene, ACVR2, were identified in colon and pancreatic cell lines and tumors with MSI. Because prostate tumors appear to have a high incidence of MSI, we analyzed prostate cancer cell lines, with and without MSI, for ACVR2 and TGFbetaR2 mutations. Our analysis of 6 prostate cell lines revealed mutations in the ACVR2 gene in 22Rv-1, LAPC-4, DU145, and LNCaP cells and mutations in the TGFbetaR2 gene in 22Rv-1 and LAPC-4. PC3 and H660 cells were wild-type for ACVR2 and TFGbetaR2. All of the ACVR2 mutations were truncating mutations, and using an activin response assay, we demonstrate that truncating mutations of the ACVR2 gene result in a significant reduction in activin mediated cell signaling. Inactivation of ACVR2 is a common event in prostate cancer cells suggesting it may play an important role in the development of prostate cancer.