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Vol. 17, Issue 6, 2811-2823, June 2006

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The Kinesin KIF1C and Microtubule Plus Ends Regulate Podosome Dynamics in Macrophages

Petra Kopp^*, Reiner Lammers, Martin Aepfelbacher, Günther Woehlke, Thomas Rudel^||, Nikolaus Machuy^||, Walter Steffen^¶, and Stefan Linder^*

*Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universität, 80336 Munich, Germany; Medizinische Klinik IV, Universität Tübingen, 72076 Tübingen, Germany; Institut für Infektionsmedizin, Universitätsklinikum Hamburg Epppendorf, 20246 Hamburg, Germany; Institut für Zellbiologie, Ludwig-Maximilians-Universität, 80336 Munich, Germany; ^||Max-Planck-Institut für Infektionsbiologie, 10117 Berlin, Germany; and ^¶Institut für Molekular- und Zellphysiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany

Submitted November 3, 2005; Revised February 24, 2006; Accepted March 9, 2006
Monitoring Editor: Paul Matsudaira

Microtubules are important for the turnover of podosomes, dynamic, actin-rich adhesions implicated in migration and invasion of monocytic cells. The molecular basis for this functional dependency, however, remained unclear. Here, we show that contact by microtubule plus ends critically influences the cellular fate of podosomes in primary human macrophages. In particular, we identify the kinesin KIF1C, a member of the Kinesin-3 family, as a plus-end–enriched motor that targets regions of podosome turnover. Expression of mutation constructs or small interfering RNA-/short hairpin RNA-based depletion of KIF1C resulted in decreased podosome dynamics and ultimately in podosome deficiency. Importantly, protein interaction studies showed that KIF1C binds to nonmuscle myosin IIA via its PTPD-binding domain, thus providing an interface between the actin and tubulin cytoskeletons, which may facilitate the subcellular targeting of podosomes by microtubules. This is the first report to implicate a kinesin in podosome regulation and also the first to describe a function for KIF1C in human cells.

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

Address correspondence to: Stefan Linder ( stefan.linder{at}med.uni-muenchen.de)

Abbreviations used: AMP-PNP, adenyl-5'-yl imidodiphosphate; CLIP, cytoplasmic linker protein; EHNA, erythro-9-[3-(2-hydroxynonyl)]adenine; KAP, kinesin-associated protein; KIF, kinesin-like-family; KLC, kinesin light chain; MALDI-TOF, matrix-assisted laser desorption ionization/time of flight; mRFP, monomeric red fluorescent protein; MTOC, microtubule-organizing center; PBD, protein tyrosine phosphatase-binding domain; PTPD, protein tyrosine phosphatase; siRNA, small interfering RNA; shRNA, short hairpin RNA

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