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Am J Physiol Cell Physiol (June 11, 2003). doi:10.1152/ajpcell.00053.2003
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Submitted on February 6, 2003
Accepted on June 2, 2003

Phosphorylation of Threonine276 in Smad4 is Involved in Transforming Growth Factor-{beta}-Induced Nuclear Accumulation

Bernard A Roelen1*, Ori S Cohen2, Malay K Raychowdhury3, Deborah N Chadee4, Ying Zhang2, John M Kyriakis4, Alessandro A Alessandrini3, and Herbert Y Lin1

1 Program in Membrane Biology, Massachusetts General Hospital, Charlestown, MA, USA; Renal Unit, Massachusetts General Hospital, Charlestown, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
2 Program in Membrane Biology, Massachusetts General Hospital, Charlestown, MA, USA; Renal Unit, Massachusetts General Hospital, Charlestown, MA, USA
3 Renal Unit, Massachusetts General Hospital, Charlestown, MA, USA
4 Molecular Cardiology Research Institute, New England Medical Center, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: b.roelen{at}nki.nl.

Smad4, the common Smad, is central for TGF-{beta} superfamily ligand signaling. Smad4 has been shown to be constitutively phosphorylated, but the site(s) of phosphorylation, the kinase(s) that performs this phosphorylation, and the significance of the phosphorylation of Smad4 are currently unknown. This report describes the identification of a consensus Erk phosphorylation site in the linker region of Smad4 at Thr 276. Our data show that Erk can phosphorylate Smad4 in vitro, but not Smad4 with mutated Thr276. Flag-tagged Smad4-T276A mutant protein accumulates less efficiently in the nucleus after stimulation by TGF-{beta}, and is less efficient in generating a transcriptional response than Smad4-wildtype protein. Tryptic phosphopeptide mapping identified a phosphopeptide in Smad4-wild type protein that was absent in phosphorylated Smad4-T276A mutant protein. Our results suggest that MAP kinase can phosphorylate Thr276 of Smad4, and that phosphorylation can lead to enhanced TGF-{beta}-induced nuclear accumulation, and as a consequence enhanced transcriptional activity of Smad4.




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