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Regulation of Smad Activity by Phosphorylation

  • Chapter
Transforming Growth Factor-β in Cancer Therapy, Volume I

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Transforming growth factor-β (TGF-β) regulates a wide variety of biological activities. Smad proteins play a major role in transducing the TGF-β family signal at the cell surface into gene regulation in the nucleus. In response to TGF-β, Smad2 and Smad3 are activated through phosphorylation by the TGF-β receptor at the C-tail SSXS motif. The activated Smad2 and Smad3 then form heteromeric complexes with Smad4, and together accumulate in the nucleus to regulate transcription of target genes. Similarly, Smad1 is activated through phosphorylation by the BMP receptor at the C-tail SSXS motif. Smad phosphatases that dephosphorylate the SSXS motifs have been identified as key regulators in the termination of the TGF-β family signals. Smad proteins are also phosphorylated by other kinases including the MAP kinase family members, cyclin-dependent kinases, protein kinase C, and Ca2+-calmodulin-dependent kinase II. Phosphorylation by these kinases regulates Smad activity in several modes, such as nuclear accumulation, DNA binding, and transcriptional activity, thus affecting proliferation, apoptosis, and other activities. Identification of the various kinases and phosphatases that phosphorylate/dephosphorylate Smads and elucidation of the mechanisms by which they regulate Smads activities help develop more effective therapies against cancer.

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Authors and Affiliations

  1. Center for Advanced Biotechnology and Medicine Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, USA

    Fang Liu PhD

  2. Cancer Institute of New Jersey, The State University of New Jersey, Piscataway, NJ, USA

    Fang Liu PhD

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Liu, F. (2008). Regulation of Smad Activity by Phosphorylation. In: Transforming Growth Factor-β in Cancer Therapy, Volume I. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-292-2_7

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  • DOI: https://doi.org/10.1007/978-1-59745-292-2_7

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