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J. Biol. Chem., Vol. 282, Issue 25, 18379-18387, June 22, 2007

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Human Tribbles-1 Controls Proliferation and Chemotaxis of Smooth Muscle Cells via MAPK Signaling Pathways^*

Hye Youn Sung, Hongtao Guan, Agnes Czibula^¶, Andrea R. King, Katalin Eder^||1, Emily Heath, S. Kim Suvarna^**, Steven K. Dower, Anthony G. Wilson, Sheila E. Francis, David C. Crossman, and Endre Kiss-Toth²

From the Cardiovascular Research Unit and Section of Infection, Inflammation and Immunity, University of Sheffield, Sheffield S10 2TN, United Kingdom, the ^**Department of Histopathology, Northern General Hospital, Sheffield S5 7AU, United Kingdom, and the ^¶Institute of Genetics and ^||Institute of Biochemistry, Biological Research Centre, H-6701 Szeged, Hungary

Migration and proliferation of smooth muscle cells are key to a number of physiological and pathological processes, including wound healing and the narrowing of the vessel wall. Previous work has shown links between inflammatory stimuli and vascular smooth muscle cell proliferation and migration through mitogen-activated protein kinase (MAPK) activation, although the molecular mechanisms of this process are poorly understood. Here we report that tribbles-1, a recently described modulator of MAPK activation, controls vascular smooth muscle cell proliferation and chemotaxis via the Jun kinase pathway. Our findings demonstrate that this regulation takes place via direct interactions between tribbles-1 and MKK4/SEK1, a Jun activator kinase. The activity of this kinase is dependent on tribbles-1 levels, whereas the activation and the expression of MKK4/SEK1 are not. In addition, tribbles-1 expression is elevated in human atherosclerotic arteries when compared with non-atherosclerotic controls, suggesting that this protein may play a role in disease in vivo. In summary, the data presented here suggest an important regulatory role for trb-1 in vascular smooth muscle cell biology.

Received for publication, November 21, 2006 , and in revised form, April 20, 2007.

^* This work was supported by the British Heart Foundation Project Grants PG/02/122 and PG/05/100 and by the Project Grant 7805 of Sheffield Hospitals Charitable Trust. 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.

¹ Supported by a short term visiting fellowship of European Federation of Immunological Societies.

² To whom correspondence should be addressed: Cardiovascular Research Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. Tel.: 44 114 271 3452; Fax: 44 114 2268898; E-mail: E.Kiss-Toth{at}sheffield.ac.uk.

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