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Molecular and Cellular Biology, August 2006, p. 5595-5602, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00352-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Phosphatidylinositol-3 Phosphatase Myotubularin-Related Protein 6 Negatively Regulates CD4 T Cells{dagger}

Shekhar Srivastava,1,4 Kyung Ko,1,4 Papiya Choudhury,1,4 Zhai Li,1,4 Amanda K. Johnson,5 Vivek Nadkarni,1,3 Derya Unutmaz,5 William A. Coetzee,1,2 and Edward Y. Skolnik1,3,4*

Departments of Pharmacology,1 Pediatric Cardiology,2 Division of Nephrology,3 The Skirball Institute, New York University School of Medicine, New York, New York,4 Vanderbilt University Medical School, Department of Microbiology and Immunology, Nashville, Tennessee5

Received 27 February 2006/ Returned for modification 28 March 2006/ Accepted 9 May 2006

Intracellular Ca2+ levels rapidly rise following cross-linking of the T-cell receptor (TCR) and function as a critical intracellular second messenger in T-cell activation. It has been relatively under appreciated that K+ channels play an important role in Ca2+ influx into T lymphocytes by helping to maintain a negative membrane potential which provides an electrochemical gradient to drive Ca2+ influx. Here we show that the Ca2+-activated K+ channel, KCa3.1, which is critical for Ca2+ influx in reactivated naive T cells and central memory T cells, requires phosphatidylinositol-3 phosphatase [PI(3)P] for activation and is inhibited by the PI(3)P phosphatase myotubularin-related protein 6 (MTMR6). Moreover, by inhibiting KCa3.1, MTMR6 functions as a negative regulator of Ca2+ influx and proliferation of reactivated human CD4 T cells. These findings point to a new and unexpected role for PI(3)P and the PI(3)P phosphatase MTMR6 in the regulation of Ca2+ influx in activated CD4 T cells and suggest that MTMR6 plays a critical role in setting a minimum threshold for a stimulus to activate a T cell.

* Corresponding author. Mailing address: The Skirball Institute, 540 First Ave., New York, NY 10016. Phone: (212) 263-7458. Fax: (212) 263-8951. E-mail: Skolnik{at}saturn.med.nyu.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2006, p. 5595-5602, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00352-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Srivastava, S., Di, L., Zhdanova, O., Li, Z., Vardhana, S., Wan, Q., Yan, Y., Varma, R., Backer, J., Wulff, H., Dustin, M. L., Skolnik, E. Y. (2009). The Class II Phosphatidylinositol 3 kinase C2{beta} Is Required for the Activation of the K+ Channel KCa3.1 and CD4 T-Cells. Mol. Biol. Cell 20: 3783-3791 [Abstract] [Full Text]  
  • Zou, J., Chang, S.-C., Marjanovic, J., Majerus, P. W. (2009). MTMR9 Increases MTMR6 Enzyme Activity, Stability, and Role in Apoptosis. J. Biol. Chem. 284: 2064-2071 [Abstract] [Full Text]  
  • Srivastava, S., Zhdanova, O., Di, L., Li, Z., Albaqumi, M., Wulff, H., Skolnik, E. Y. (2008). Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1. Proc. Natl. Acad. Sci. USA 105: 14442-14446 [Abstract] [Full Text]  
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  • Choudhury, P., Srivastava, S., Li, Z., Ko, K., Albaqumi, M., Narayan, K., Coetzee, W. A., Lemmon, M. A., Skolnik, E. Y. (2006). Specificity of the Myotubularin Family of Phosphatidylinositol-3-phosphatase Is Determined by the PH/GRAM Domain. J. Biol. Chem. 281: 31762-31769 [Abstract] [Full Text]  


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