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RECEPTORS AND SIGNAL TRANSDUCTION

Phosphorylation of threonine 276 in Smad4 is involved in transforming growth factor--induced nuclear accumulation

¹Program in Membrane Biology and ²Renal Unit, Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Charlestown 02129; and ³Molecular Cardiology Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111

Submitted 6 February 2003 ; accepted in final form 2 June 2003

Smad4, the common Smad, is central for transforming growth factor (TGF)- superfamily ligand signaling. Smad4 has been shown to be constitutively phosphorylated (Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin C-H, Miyazono K, and ten Dijke P. EMBO J 16: 5353-5362, 1997), 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 Thr²⁷⁶. 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- and is less efficient in generating a transcriptional response than Smad4 wild-type 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--induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of Smad4.

signal transduction; mitogen-activated protein kinase; phosphopeptide mapping; extracellular signal-regulated kinase phosphorylation site; luciferase reporter

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