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J. Biol. Chem., Vol. 279, Issue 45, 46588-46594, November 5, 2004

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Protein Phosphatase 4 Interacts with and Down-regulates Insulin Receptor Substrate 4 following Tumor Necrosis Factor- Stimulation^*

Kathie A. Mihindukulasuriya, Guisheng Zhou¶, Jun Qin||, and Tse-Hua Tan**

From the Department of Immunology and ^||Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030

Protein phosphatase 4 (PP4; also named PPX or PPP4) is a PP2A-related protein serine/threonine phosphatase with important roles in a variety of cellular processes such as microtubule growth/organization, apoptosis, tumor necrosis factor (TNF)- signaling, and activation of c-Jun N-terminal kinase and NF-B. To further investigate the cellular functions of PP4, we isolated and identified PP4-interacting proteins using a proteomic approach. We found that insulin receptor substrate 4 (IRS-4) interacted with PP4 and that this interaction was enhanced following TNF- stimulation. We also found that PP4, but not PP2A, down-regulated IRS-4 in a phosphatase activity-dependent manner. Pulse-chase analysis revealed that PP4 decreased the half-life of IRS-4 from 4 to 1 h. Moreover, we found that TNF- stimulated a PP4-dependent degradation of IRS-4, as indicated by the blockage of the degradation by a potent PP4 inhibitor (okadaic acid) and a phosphatase-dead PP4 mutant (PP4-RL). Taken together, our studies indicate that IRS-4 is subject to regulation by TNF- and that PP4 mediates TNF--induced degradation of IRS-4.

Received for publication, July 16, 2004 , and in revised form, August 23, 2004.

^* This work was supported by National Institutes of Health (NIH) Grant R01-CA87076 (to T.-H. T.), American Heart Association, Texas Affiliate, Beginning Grant-in-aid 0465156Y (to G. Z.), United States Army Breast Cancer Research Program Predoctoral Fellowship DAMD 17-011-0139, and NIH Training Grant T32-AI07495 (to K. A. M.). 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.

This paper is dedicated to the memory of Suzanne Robertson, whose kindness and helpfulness bettered the lives of all of those who had the privilege to work with her.

These two authors contributed equally to this work.

^¶ To whom correspondence may be addressed: Dept. of Immunology, Baylor College of Medicine, One Baylor Plaza, M929, Houston, TX 77030. E-mail: guisheng{at}bcm.tmc.edu. ** To whom correspondence may be addressed: Dept. of Immunology, Baylor College of Medicine, One Baylor Plaza, M929, Houston, TX 77030. E-mail: ttan{at}bcm.tmc.edu.

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