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Proc Natl Acad Sci U S A. July 10, 2012; 109 (28): E1947-56.

Dynamics of TGF-β signaling reveal adaptive and pulsatile behaviors reflected in the nuclear localization of transcription factor Smad4.

Warmflash A , Zhang Q , Sorre B , Vonica A , Siggia ED , Brivanlou AH .

The TGF-β pathway plays a vital role in development and disease and regulates transcription through a complex composed of receptor-regulated Smads (R-Smads) and Smad4. Extensive biochemical and genetic studies argue that the pathway is activated through R-Smad phosphorylation; however, the dynamics of signaling remain largely unexplored. We monitored signaling and transcriptional dynamics and found that although R-Smads stably translocate to the nucleus under continuous pathway stimulation, transcription of direct targets is transient. Surprisingly, Smad4 nuclear localization is confined to short pulses that coincide with transcriptional activity. Upon perturbation, the dynamics of transcription correlate with Smad4 nuclear localization rather than with R-Smad activity. In Xenopus embryos, Smad4 shows stereotyped, uncorrelated bursts of nuclear localization, but activated R-Smads are uniform. Thus, R-Smads relay graded information about ligand levels that is integrated with intrinsic temporal control reflected in Smad4 into the active signaling complex.

PubMed ID: 22689943
PMC ID: PMC3396545
Article link: Proc Natl Acad Sci U S A.
Grant support: R01 HD32105 NICHD NIH HHS , R01 GM101653 NIGMS NIH HHS , R01 GM101653 NIGMS NIH HHS , R01 HD032105 NICHD NIH HHS , R01 HD32105 NICHD NIH HHS

Genes referenced: hist2h2be nodal smad1 smad2 smad4.1 smad4.2 smad7

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