Crossing Smads

Jeffrey L. Wrana

Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Medical Genetics and Microbiology, University of Toronto, Canada. E-mail: wrana{at}mshri.on.ca

The transforming growth factor–ß (TGF-ß) superfamily is a group of polypeptide growth factors that are secreted from cells as dimeric molecules. Members of this family regulate early development, organogenesis, and homeostasis, and mutations of this pathway are associated with human diseases (including cancer) and with hereditary conditions such as persistent Mullerian duct syndrome, Hunter-Thompson acromesomelic chondrodysplasia, and hereditary hemorrhagic telangiectasia. The TGF-ß family regulates cellular function by activating a unique family of transmembrane serine-threonine kinase receptors. These receptors then translate binding of the TGF-ß ligand into an intracellular signal. This is achieved by the activation of a family of intracellular signal transduction molecules known as Smads. When activated by the receptor, different types of Smads assemble into heteromeric complexes and translocate into the nucleus, where they interact with a host of DNA binding proteins to regulate transcription. Thus, Smads transmit TGF-ß signals directly from the cell surface receptor to nuclear transcription factors. In the nucleus, one class of Smad partners, exemplified by the DNA binding protein FAST, cannot regulate transcription in the absence of Smad protein. However, when Smads bind to FAST protein, they cause activation of genes that contain FAST binding sites in their promoters. In these cases, Smads represent a primary regulatory signal. In contrast, members of the second group of Smad partners control transcription in the absence of Smads and can be regulated by other signaling pathways. In these cases, Smads represent a secondary signal that augments transcription (or, in some examples, represses transcription) mediated by these partners. Smads can be thought of as transcriptional comodulators that modify the output of these other signaling pathways. This "crosstalk" in the nucleus allows Smads to control a diverse array of transcriptional outputs in response to TGF-ß stimulation of cells.

The editors suggest the following Related Resources on Science sites:

In Science Signaling

EDITORS' CHOICE
BONE
Does Heparin BMP Up Bone Formation?

(15 August 2006)
Sci. STKE 2006 (348), tw278. [DOI: 10.1126/stke.3482006tw278]
 |  Abstract »

REVIEWS
TGF-ß Superfamily Signaling and Left-Right Asymmetry

Malcolm Whitman and Mark Mercola (9 January 2001)
Sci. STKE 2001 (64), re1. [DOI: 10.1126/stke.2001.64.re1]
 |  Gloss »  |  Abstract »  |  Full Text »  |  PDF »

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES: