Smad 4 is a member of the Mothers Against Dpp (MAD)-related family of proteins. So far, eight Smads have been identified and can be divided in 3 subgroups based on their structure and functions; pathway-restricted, common mediator and inhibitory Smad. Smad 4 is the common Smad (co-Smad). Previously identified as the tumor suppressor DPC4 (deleted in pancreatic carcinoma, locus 4), Smad 4 is functionally distinct among the Smad family, and is required for the assembly and transcriptional activation of diverse, Smad-DNA complexes. In contrast to the R-Smads, Smad 4 is not regulated by phosphorylation, but acts as a common mediator of TGF-Beta, activin, and bone morphogenetic protein signaling responses. Smad 4 is frequently inactivated in pancreatic, biliary and colorectal tumors.