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J. Biol. Chem., Vol. 278, Issue 30, 27853-27863, July 25, 2003
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Family Signaling*
From the
Departments of Growth and Development, and Anatomy, Programs in Cell
Biology and Developmental Biology, University of California, San Francisco,
California 94143-0640 and the Department of Cell
Biology, Cellular and Molecular Biology Program, University of Alabama,
Birmingham, Alabama 35294-0005
Transforming growth factor-
(TGF-) and TGF--related
factors regulate cell growth, differentiation, and apoptosis, and play key
roles in normal development and tumorigenesis. TGF- family-induced
changes in gene expression are mediated by serine/threonine kinase receptors
at the cell surface and Smads as intracellular effectors. Receptor-activated
Smads combine with a common Smad4 to translocate into the nucleus where they
cooperate with other transcription factors to activate or repress
transcription. The activities of the receptor-activated Smads are controlled
by post-translational modifications such as phosphorylation and
ubiquitylation. Here we show that Smad4 is modified by sumoylation.
Sumoylation of Smad4 was enhanced by the conjugating enzyme Ubc9 and members
of the PIAS family of SUMO ligases. A major sumoylation site in Smad4 was
localized to Lys-159 in its linker segment with an additional site at Lys-113
in the MH-1 domain. Increased sumoylation in the presence of the PIASy E3
ligase correlated with targeting of Smad4 to subnuclear speckles that contain
SUMO-1 and PIASy. Replacement of lysines 159 and 113 by arginines or increased
sumoylation enhanced the stability of Smad4, and transcription in mammalian
cells and Xenopus embryos. These observations suggest a role for
Smad4 sumoylation in the regulation of TGF- signaling through Smads.
Received for publication, February 19, 2003 , and in revised form, May 6, 2003.
* This work was supported in part by National Institutes of Health Grants CA63101 and HL62301 (to R. D.) and a Howard Hughes Medical Institute Institutional Career Development Award (to C. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by a fellowship from the Tobacco-related Disease Research Program
of California.
¶ Supported by a fellowship from the National Institutes of Health.
|| To whom correspondence should be addressed: Dept. of Growth and Development, University of California, San Francisco, CA 94143-0640. Tel.: 415-476-7322; Fax: 415-476-1499; E-mail: derynck{at}itsa.ucsf.edu.
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