MADR2 MAPS TO 18Q21 AND ENCODES A TGF-BETA-REGULATED MAD-RELATED PROTEIN THAT IS FUNCTIONALLY MUTATED IN COLORECTAL-CARCINOMA

The MAD-related (MADR) family of proteins are essential components in the signaling pathways of serine/threonine kinase receptors for the tr ansforming growth factor beta (TGF beta) superfamily. We demonstrate t hat MADR2 is specifically regulated by TGF beta and not bone morphogen etic proteins. The gene for MADR2 was found to reside on chromosome 18 q21, near DPC4, another MADR protein implicated in pancreatic cancer. Mutational analysis of MADR2 in sporadic tumors identified four missen se mutations in colorectal carcinomas, two of which display a loss of heterozygosity. Biochemical and functional analysis of three of these demonstrates that the mutations are inactivating. These findings sugge st that MADR2 is a tumor suppressor and that mutations acquired in col orectal carcinomas may function to disrupt TGF beta signaling.