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J. Biol. Chem., Vol. 278, Issue 22, 20029-20036, May 30, 2003

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The C-terminal Kinase Domain of the p34cdc2-related PITSLRE Protein Kinase (p110C) Associates with p21-activated Kinase 1 and Inhibits Its Activity during Anoikis^*

She Chen  , Xianglei Yin  ¶, Xiaoyu Zhu ¶, Jun Yan ¶, Shuying Ji ¶, Chun Chen ¶, Mingmei Cai ¶, Songwen Zhang ¶, Hongliang Zong ¶, Yun Hu ¶, Zhenghong Yuan ||, Zonghou Shen  and Jianxin Gu ¶ **

From the ^¶Gene Research Center, the Department of Biochemistry, and the ^||Department of Molecular Virus, Shanghai Medical Center, Fudan University (formerly the Shanghai Medical University), Shanghai 200032, People's Republic of China

The PITSLRE protein kinases are parts of the large family of p34cdc2-related kinases. During apoptosis induced by some stimuli, specific PITSLRE isoforms are cleaved by caspase to produce a protein that contains the C-terminal kinase domain of the PITSLRE proteins (p110C). The p110C induces apoptosis when it is ectopically expressed in Chinese hamster ovary cells. In our study, similar induction of this p110C was observed during anoikis in NIH3T3 cells. To investigate the molecular mechanism of apoptosis mediated by p110C, we used the yeast two-hybrid system to screen a human fetal liver cDNA library and identified p21-activated kinase 1 (PAK1) as an interacting partner of p110C. The association of p110C with PAK1 was further confirmed by in vitro binding assay, in vivo coimmunoprecipitation, and confocal microscope analysis. The interaction of p110C with PAK1 occurred within the residues 210–332 of PAK1. Neither association between p58^PITSLRE or p110^PITSLRE and PAK1 nor association between p110C and PAK2 or PAK3 was observed. Anoikis was increased and PAK1 activity was inhibited when NIH3T3 cells were transfected with p110C. Furthermore, the binding of p110C with PAK1 and inhibition of PAK1 activity were also observed during anoikis. Taken together, these data suggested that PAK1 might participate in the apoptotic pathway mediated by p110C.

Received for publication, January 24, 2003

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) U04824.

^* This work was supported by 863 Program 2001AA234031 and Chinese State Basic Research Foundation Grant G1999054105. 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 86-21-5423-7704; Fax: 86-21-6416-4489; E-mail: jxgu{at}shmu.edu.cn.

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