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J. Biol. Chem., Vol. 282, Issue 19, 13954-13965, May 11, 2007

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Protein Phosphatase-1 Modulates the Function of Pax-6, a Transcription Factor Controlling Brain and Eye Development^*

Qin Yan¹, Wen-Bin Liu¹, Jichao Qin, Jinping Liu, He-Ge Chen, Xiaoqin Huang, Lili Chen, Shuming Sun, Mi Deng, Lili Gong, Yong Li, Lan Zhang, Yan Liu, Hao Feng, Yamei Xiao, Yun Liu, and David W.-C. Li^¶2

From the Departments of Biochemistry and Molecular Biology and ^¶Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198 and the College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China

Pax-6 is an evolutionarily conserved transcription factor and acts high up in the regulatory hierarchy controlling eye and brain development in humans, mice, zebrafish, and Drosophila. Previous studies have shown that Pax-6 is a phosphoprotein, and its phosphorylation by ERK, p38, and homeodomain-interacting protein kinase 2 greatly enhances its transactivation activity. However, the protein phosphatases responsible for the dephosphorylation of Pax-6 remain unknown. Here, we present both in vitro and in vivo evidence to show that protein serine/threonine phosphatase-1 is a major phosphatase that directly dephosphorylates Pax-6. First, purified protein phosphatase-1 directly dephosphorylates Pax-6 in vitro. Second, immunoprecipitation-linked Western blot revealed that both protein phosphatase-1 and protein phosphatase-1 interact with Pax-6. Third, overexpression of protein phosphatase-1 in human lens epithelial cells leads to dephosphorylation of Pax-6. Finally, inhibition of protein phosphatase-1 activity by calyculin A or knockdown of protein phosphatase-1 and protein phosphatase-1 by RNA interference leads to enhanced phosphorylation of Pax-6. Moreover, our results also demonstrate that dephosphorylation of Pax-6 by protein phosphatase-1 significantly modulates its function in regulating expression of both exogenous and endogenous genes. These results demonstrate that protein phosphatase 1 acts as a major phosphatase to dephosphorylate Pax-6 and modulate its function.

Received for publication, December 14, 2006 , and in revised form, March 16, 2007.

^* This work is supported in part by NEI, National Institutes of Health, Grant 1 R01EY15765, the University of Nebraska startup funds, and the Lotus Scholar Program Funds from Hunan Province Government and Hunan Normal University. 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.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870. Tel.: 402-559-5073; Fax: 402-559-6650; E-mail: dwli1688{at}hotmail.com.

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