Signal transduction of TGF-? superfamily members is regulated by Smad proteins. In particular, Smads influence specific gene transcription by relaying signals from the cell membrane to the nucleus. Smad4 plays an essential role in TGF-?-induced transcriptional activation wherein phosphorylated receptor-associated Smads associate with Smad4. Furthermore, SMIF (Smad4-intereacting protein) and Smad4 complex with TGF-? and BMP4. An increase in Smad4 concentration increases the translocation of this complex to the nucleus. SMIF and Smad4 interact directly through a EVH1/WH1 domain on SMIF and a proline-rich activation domain on Smad4. Smad4 is essential to nuclear translocation of SMIF as deletion of the Smad4-interacting domain (located in the N-terminal 100 amino acids) of SMIF eliminates TGF-?-induced nuclear translocation of SMIF (1). The human SMIF gene is ubiquitously expressed and encodes a protein with a relative molecular mass of 70 kDa.