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Crossing Smads

The transforming growth factor–β (TGF-β) 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-β family regulates cellular function by activating a unique family of transmembrane serine-threonine kinase receptors. These receptors then translate binding of the TGF-β 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-β 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-β stimulation of cells.

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Classifications


Resource Type: Bibliography, Diagram, Illustration, Journal article/Issue, Review
Audience Level: Undergraduate upper division 15-16, Graduate, Professional (degree program)

Author and Copyright


Authors and Editors: Jeffrey L. Wrana of Mount Sinai Hospital and Department of Medical Genetics and Microbiology, University of Toronto
Publisher: American Association for the Advancement of Science
Format: application/pdf, image/gif, image/jpeg, text/html
Copyright and other restrictions: Yes
Cost: Yes

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STKE/Science Signaling


     
   

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