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Vol. 18, Issue 12, 5069-5080, December 2007

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Type I PIP Kinase Is a Novel Uropod Component that Regulates Rear Retraction during Neutrophil Chemotaxis

Mary A. Lokuta^*,, Melissa A. Senetar^,, David A. Bennin^*, Paul A. Nuzzi, Keefe T. Chan, Vanessa L. Ott^*, and Anna Huttenlocher^*,

Departments of Medical Microbiology and Immunology and *Pediatrics, University of Wisconsin, Madison, WI 53706

Submitted May 10, 2007; Revised September 21, 2007; Accepted September 28, 2007
Monitoring Editor: Josephine Adams

Cell polarization is necessary for directed migration and leukocyte recruitment to inflamed tissues. Recent progress has been made in defining the molecular mechanisms that regulate chemoattractant-induced cell polarity during chemotaxis, including the contribution of phosphoinositide 3-kinase (PI3K)-dependent phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P₃] synthesis at the leading edge. However, less is known about the molecular composition of the cell rear and how the uropod functions during cell motility. Here, we demonstrate that phosphatidylinositol phosphate kinase type I (PIPKI661), which generates PtdIns(4,5)P₂, is enriched in the uropod during chemotaxis of primary neutrophils and differentiated HL-60 cells (dHL-60). Using time-lapse microscopy, we show that enrichment of PIPKI661 at the cell rear occurs early upon chemoattractant stimulation and is persistent during chemotaxis. Accordingly, we were able to detect enrichment of PtdIns(4,5)P₂ at the uropod during chemotaxis. Overexpression of kinase-dead PIPKI661 compromised uropod formation and rear retraction similar to inhibition of ROCK signaling, suggesting that PtdIns(4,5)P₂ synthesis is important to elicit the backness response during chemotaxis. Together, our findings identify a previously unknown function for PIPKI661 as a novel component of the backness signal that regulates rear retraction during chemotaxis.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: Anna Huttenlocher (huttenlocher{at}wisc.edu).

Abbreviations used: C5a, Complement factor 5a; DIC, differential interference contrast microscopy; dHL-60, differentiated HL-60; fMLP, formyl-Met-Leu-Phe; PMN, polymorphonuclear cells; PI3K, phosphoinositide 3-kinase; PtdIns(3,4,5)P₃, phosphatidylinositol (3,4,5)-trisphosphate; PtdIns(4,5)P₂, phosphatidylinositol (4,5)-bisphosphate; PIPKI661, Type I661 phosphatidylinositol phosphate kinase; KD, kinase-dead; GFP, green fluorescent protein.

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