HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 285/4/C823    most recent 00053.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Roelen, B. A. J. Articles by Lin, H. Y. Search for Related Content PubMed PubMed Citation Articles by Roelen, B. A. J. Articles by Lin, H. Y.

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

This article has been cited by other articles:

				G. Ramey, J.-C. Deschemin, and S. Vaulont Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes Haematologica, June 1, 2009; 94(6): 765 - 772. [Abstract] [Full Text] [PDF]

				K. Suzuki, M. C. Wilkes, N. Garamszegi, M. Edens, and E. B. Leof Transforming Growth Factor {beta} Signaling via Ras in Mesenchymal Cells Requires p21-Activated Kinase 2 for Extracellular Signal-Regulated Kinase-Dependent Transcriptional Responses Cancer Res., April 15, 2007; 67(8): 3673 - 3682. [Abstract] [Full Text] [PDF]

				A. Buck, M. Buchholz, M. Wagner, G. Adler, T. Gress, and V. Ellenrieder The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor {beta}-Induced Growth Inhibition That Is Inactivated in Pancreatic Cancer Mol. Cancer Res., November 1, 2006; 4(11): 861 - 872. [Abstract] [Full Text] [PDF]

				M. Liang, Y.-Y. Liang, K. Wrighton, D. Ungermannova, X.-P. Wang, F. C. Brunicardi, X. Liu, X.-H. Feng, and X. Lin Ubiquitination and Proteolysis of Cancer-Derived Smad4 Mutants by SCFSkp2 Mol. Cell. Biol., September 1, 2004; 24(17): 7524 - 7537. [Abstract] [Full Text] [PDF]