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J. Biol. Chem., Vol. 280, Issue 7, 5676-5681, February 18, 2005

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Vinculin Controls PTEN Protein Level by Maintaining the Interaction of the Adherens Junction Protein -Catenin with the Scaffolding Protein MAGI-2^*

M. Cecilia Subauste, Perihan Nalbant, Eileen D. Adamson¶, and Klaus M. Hahn||

From the Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, ^¶The Burnham Institute, La Jolla Cancer Research Center, La Jolla, California 92037, and ^||Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7365

PTEN is a frequently mutated tumor suppressor in malignancies. Interestingly, some malignancies exhibit undetectable PTEN protein without mutations or loss of PTEN mRNA. The cause(s) for this reduction in PTEN is unknown. Cancer cells frequently exhibit loss of cadherin, -catenin, -catenin and/or vinculin, key elements of adherens junctions. Here we show that F9 vinculin-null (vin^–/–) cells lack PTEN protein despite normal PTEN mRNA levels. Their PTEN protein expression was restored by transfection with vinculin or by inhibition of PTEN degradation. F9 vin^–/– cells express PTEN protein upon transfection with a vinculin fragment (amino acids 243–1066) that is capable of interacting with -catenin but unable to target into focal adhesions. On the other hand, disruption of adherens junctions with an E-cadherin blocking antibody reduced PTEN protein to undetectable levels in wild-type F9 cells. PTEN protein levels were restored in F9 vin^–/– cells upon transfection with an E-cadherin--catenin fusion protein, which targets into adherens junctions and interacts with -catenin in F9 vin^–/– cells. -Catenin is known to interact with MAGI-2. MAGI-2 interaction with PTEN in the cell membrane is known to prevent PTEN protein degradation. Thus, MAGI-2 overexpression in F9 vin^–/– cells restored PTEN protein levels. Moreover, expression of vinculin mutants that reinstated the disrupted interactions of -catenin with MAGI-2 in F9 vin^–/– cells also restored PTEN protein levels. These studies indicate that PTEN protein levels are dependent on the maintenance of -catenin-MAGI-2 interaction, in which vinculin plays a critical role.

Received for publication, May 19, 2004 , and in revised form, November 30, 2004.

^* This work was supported by National Institutes of Health Grants AI 01684 (to M. C. S.), CA 67888 (to E. D. A.), and AG 15430 (to K. M. H.). This is Scripps manuscript number 15911-CB. 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.

To whom correspondence should be addressed: Dept. of Cell Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-7108; Fax: 858-784-7333; E-mail: mcsub{at}scripps.edu.

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