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Molecular and Cellular Biology, January 2007, p. 79-91, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00799-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Conditional Knockout Mice Reveal an Essential Role of Protein Phosphatase 4 in Thymocyte Development and Pre-T-Cell Receptor Signaling{triangledown}

Jr-Wen Shui,1 Mickey C.-T. Hu,2 and Tse-Hua Tan1*

Department of Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030,1 Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 770302

Received 5 May 2006/ Returned for modification 18 June 2006/ Accepted 4 October 2006

Okadaic acid-sensitive serine/threonine phosphatases have been shown to regulate interleukin-2 transcription and T-cell activation. Okadaic acid inhibits protein phosphatase 4 (PP4), a novel PP2A-related serine/threonine phosphatase, at a 50% inhibitory concentration (IC50) comparable to that for PP2A. This raises the possibility that some cellular functions of PP2A, determined in T cells by using okadaic acid, may in fact be those of PP4. To investigate the in vivo roles of PP4 in T cells, we generated conventional and T-cell-specific PP4 conditional knockout mice. We found that the ablation of PP4 led to the embryonic lethality of mice. PP4 gene deletion in the T-cell lineage resulted in aberrant thymocyte development, including T-cell arrest at the double-negative 3 stage (CD4– CD8– CD25+ CD44–), abnormal thymocyte maturation, and lower efficacy of positive selection. PP4-deficient thymocytes showed decreased proliferation and enhanced apoptosis in vivo. Analysis of pre-T-cell receptor (pre-TCR) signaling further revealed impaired calcium flux and phospholipase C-{gamma}1-extracellular signal-regulated kinase activation in the absence of PP4. Anti-CD3 injection in PP4-deficient mice led to enhanced thymocyte apoptosis, accompanied by increased proapoptotic Bim but decreased antiapoptotic Bcl-xL protein levels. In the periphery, antigen-specific T-cell proliferation and T-cell-mediated immune responses in PP4-deficient mice were dramatically compromised. Thus, our results indicate that PP4 is essential for thymocyte development and pre-TCR signaling.

* Corresponding author. Mailing address: Department of Immunology, M929, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-4665. Fax: (713) 798-3033. E-mail: ttan{at}bcm.edu.

{triangledown} Published ahead of print on 23 October 2006.

Molecular and Cellular Biology, January 2007, p. 79-91, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00799-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Toyo-oka, K., Mori, D., Yano, Y., Shiota, M., Iwao, H., Goto, H., Inagaki, M., Hiraiwa, N., Muramatsu, M., Wynshaw-Boris, A., Yoshiki, A., Hirotsune, S. (2008). Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation. JCB 180: 1133-1147 [Abstract] [Full Text]  


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