SMAD

Synonym :

Structure/Function

SMADs are evolutionarily conserved proteins identified as mediators of transcriptional activation by members of the TGF-beta superfamily of cytokines ,including TGF-beta , Activins (see: Activin A ), and BMP . Upon activation these proteins directly translocate to the nucleus where they may activate transcription.

each SMAD proteins have been characterized so far in vertebrates.

SMAD-1 is the human homologue of Drosophila Mad (Mad =Mothers against decapentaplegic ) and the related Caenorhabditis elegans gene Sma. Microinjection of SMAD-1 mRNA into Xenopus laevis embryo animal caps mimics the mesoderm-ventralizing effects of BMP-4 . SMAD-1 has been shown to move into the nucleus in response to BMP-4 .

SMAD-2 has been shown to mimic the effects of Activin A in in mammalian cells. SMAD-1 and SMAD-2 are broadly expressed in human tissues.SMAD-2 has been shown to be mutated in some colon and lung human cancers.

SMAD-3 is a close homologue of SMAD-2 ) and the related proteinDPC-4 , a tumour-suppressor gene product. SMAD-2 is closely linked to DPC-4 on chromosome 18q21.1, a region often deleted in human cancers. SMAD-3 and DPC-4 proteins mediate TGF-beta actions. DPC-4 has been shown to be essential for the function of SMAD-1 and SMAD-2 in pathways that signal mesoderm induction and patterning in Xenopus laevis embryos. It is involved also in antimitogenic and transcriptional responses in breast epithelial cells. DPC-4 associates with SMAD-1 in response to BMP and with SMAD-2 in response to activin A or TGF-beta .

SMAD-3 has been shown to participate in transcriptional activation by multiple agonists.Dominant-negative SMAD-3 , but not other dominant-negative SMAD proteins, reduce stimulation of the plasminogen activator inhibitor-1 (PAI-1) and other gene promoters by phorbol esters ,cAMP, and PDGF .

SMAD-4 has been shown to be mutated in human cancers. SMAD-5 andSMAD-6 sequences have been cloned. An analysis of various tumors demonstrates that mutations in various SMAD genes do not, in general, account for the widespread resistance to TGF-beta that is found in human tumors.

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Sequence Information

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