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Molecular and Cellular Biology, May 2005, p. 3956-3966, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.3956-3966.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The LIM Protein Ajuba Regulates Phosphatidylinositol 4,5-Bisphosphate Levels in Migrating Cells through an Interaction with and Activation of PIPKI{alpha}{dagger}

Marina Kisseleva,1,{ddagger} Yungfeng Feng,1,{ddagger} Michael Ward,2 Chunhua Song,3 Richard A. Anderson,3 and Gregory D. Longmore1*

Departments of Medicine and Cell Biology,1 Anatomy and Neurobiology, Washington University, St. Louis, Missouri,2 Department of Pharmacology, University of Wisconsin, Madison, Wisconsin3

Received 31 May 2004/ Returned for modification 16 August 2004/ Accepted 14 February 2005

The phosphoinositide phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] regulates the activity of many actin-binding proteins and as such is an important modulator of cytoskeleton organization during cell migration, for example. In migrating cells actin remodeling is tightly regulated and localized; therefore, how the PI(4,5)P2 level is spatially and temporally regulated is crucial to understanding how it controls cell migration. Here we show that the LIM protein Ajuba contributes to the cellular regulation of PI(4,5)P2 levels by interacting with and activating the enzymatic activity of the PI(4)P 5-kinase (PIPKI{alpha}), the predominant enzyme in the synthesis of PI(4,5)P2, in a migration stimulus-regulated manner. In migrating primary mouse embryonic fibroblasts (MEFs) from Ajuba–/– mice the level of PI(4,5)P2 was decreased with a corresponding increase in the level of the substrate PI(4)P. Reintroduction of Ajuba into these cells normalized PI(4,5)P2 levels. Localization of PI(4,5)P2 synthesis and PIPKI{alpha} in the leading lamellipodia and membrane ruffles, respectively, of migrating Ajuba–/– MEFs was impaired. In vitro, Ajuba dramatically activated the enzymatic activity of PIPKI{alpha} while inhibiting the activity of PIPKIIß. Thus, in addition to its effects upon Rac activity Ajuba can also influence cell migration through regulation of PI(4,5)P2 synthesis through direct activation of PIPKI{alpha} enzyme activity.

* Corresponding author. Mailing address: Department of Medicine and Cell Biology, Washington University, 660 S. Euclid Avenue, St. Louis, MO 63110-1010. Phone: (314) 362-8834. Fax: (314) 263-8826. E-mail: glongmor{at}im.wustl.edu.

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

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, May 2005, p. 3956-3966, Vol. 25, No. 10
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.10.3956-3966.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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