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J. Biol. Chem., Vol. 281, Issue 13, 8313-8316, March 31, 2006

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TSC1 Stabilizes TSC2 by Inhibiting the Interaction between TSC2 and the HERC1 Ubiquitin Ligase^*

Huira Chong-Kopera^¶12, Ken Inoki¹, Yong Li¹, Tianqing Zhu, Francesc R. Garcia-Gonzalo^||, Jose Luis Rosa^||3, and Kun-Liang Guan^¶4

From the Life Sciences Institute, Department of Biological Chemistry, and ^¶Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109 and the ^||Department de Ciències Fisiològiques II, IDIBELL, Campus de Bellvitge, Universitat de Barcelona, 08907 Barcelona, Spain

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by hamartoma formation in various organs. Two genes responsible for the disease, TSC1 and TSC2, have been identified. The TSC1 and TSC2 proteins, also called hamartin and tuberin, respectively, have been shown to regulate cell growth through inhibition of the mammalian target of rapamycin pathway. TSC1 is known to stabilize TSC2 by forming a complex with TSC2, which is a GTPase-activating protein for the Rheb small GTPase. We have identified HERC1 as a TSC2-interacting protein. HERC1 is a 532-kDa protein with an E3 ubiquitin ligase homology to E6AP carboxyl terminus (HECT) domain. We observed that the interaction of TSC1 with TSC2 appears to exclude TSC2 from interacting with HERC1. Disease mutations in TSC2, which result in its destabilization, allow binding to HERC1 in the presence of TSC1. Our study reveals a potential molecular mechanism of how TSC1 stabilizes TSC2 by excluding the HERC1 ubiquitin ligase from the TSC2 complex. Furthermore, these data reveal a possible biochemical basis of how certain disease mutations inactivate TSC2.

Received for publication, November 21, 2005 , and in revised form, February 3, 2006.

^* This work was supported in part by grants from the National Institutes of Health (to K.-L. G.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ These authors made equal contributions.

² Supported by the National Institutes of Health Multidisciplinary Research Award T32-AG00114-18.

³ Supported by grants from MEC (BFU-2004-06329/BMC) and the European Union (FEDER).

⁴ To whom correspondence should be addressed. E-mail: kunliang{at}umich.edu.

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