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Originally published In Press as doi:10.1074/jbc.M704512200 on December 14, 2007
J. Biol. Chem., Vol. 283, Issue 7, 4004-4013, February 15, 2008
Serine 88 Phosphorylation of the 8-kDa Dynein Light Chain 1 Is a Molecular Switch for Its Dimerization Status and Functions*
Chunying Song 1,
Wenyu Wen 1,
Suresh K. Rayala 1,
Mingzhi Chen¶,
Jianpeng Ma¶,
Mingjie Zhang 2, and
Rakesh Kumar ||3
From the
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, the Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, the ¶Verna and Marrs McLean Department of Biochemistry and Molecular Biology and the ||Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030
Dynein light chain 1 (DLC1, also known as DYNLL1, LC8, and PIN), a ubiquitously expressed and highly conserved protein, participates in a variety of essential intracellular events. Transition of DLC1 between dimer and monomer forms might play a crucial role in its function. However, the molecular mechanism(s) that control the transition remain unknown. DLC1 phosphorylation on Ser88 by p21-activated kinase 1 (Pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with Bim and the stability of Bim. Here we discovered that phosphorylation of Ser88, which juxtapose each other at the interface of the DLC dimer, disrupts DLC1 dimer formation and consequently impairs its interaction with Bim. Overexpression of a Ser88 phosphorylation-inactive DLC1 mutant in mammary epithelium cells and in a transgenic animal model caused apoptosis and accelerated mammary gland involution, respectively, with increased Bim levels. Structural and biophysical studies suggested that phosphorylation-mimicking mutation leads to dissociation of the DLC1 dimer to a pure folded monomer. The phosphorylation-induced DLC1 monomer is incapable of binding to its substrate Bim. These findings reveal a previously unrecognized regulatory mechanism of DLC1 in which the Ser88 phosphorylation acts as a molecular switch for the transition of DLC1 from dimer to monomer, thereby modulating its interaction with substrates and consequently regulating the functions of DLC1.
Received for publication, June 1, 2007
, and in revised form, November 19, 2007.
* This work was supported in part by National Institutes of Health Grants CA80066 and CA90970 (to R. K.) and grants from the Research Grants Council of Hong Kong (to M. Z.). 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.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S8.
1 These authors contributed equally to this work.
2 To whom correspondence may be addressed. E-mail: mzhang{at}ust.hk. 3 To whom correspondence may be addressed. E-mail: rkumar{at}mdanderson.org.

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Copyright © 2008 by the American Society for Biochemistry and Molecular Biology.
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