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Published online July 7, 2008
doi:10.1083/jcb.200801042
The Journal of Cell Biology, Vol. 182, No. 1, 157-169
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Oikawa et al.
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Article

 Sequential signals toward podosome formation in NIH-src cells

Tsukasa Oikawa1, Toshiki Itoh2, and Tadaomi Takenawa1

1 Division of Lipid Biochemistry and 2 Division of Membrane Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan

Correspondence to Tadaomi Takenawa: takenawa{at}med.kobe-u.ac.jp

Podosomes (also termed invadopodia in cancer cells) are actin-rich adhesion structures with matrix degradation activity that develop in various cell types. Despite their significant physiological importance, the molecular mechanism of podosome formation is largely unknown. In this study, we investigated the molecular mechanisms of podosome formation. The expression of various phosphoinositide-binding domains revealed that the podosomes in Src-transformed NIH3T3 (NIH-src) cells are enriched with PtdIns(3,4)P2, suggesting an important role of this phosphoinositide in podosome formation. Live-cell imaging analysis revealed that Src-expression stimulated podosome formation at focal adhesions of NIH3T3 cells after PtdIns(3,4)P2 accumulation. The adaptor protein Tks5/FISH, which is essential for podosome formation, was found to form a complex with Grb2 at adhesion sites in an Src-dependent manner. Further, it was found that N-WASP bound all SH3 domains of Tks5/FISH, which facilitated circular podosome formation. These results indicate that augmentation of the N-WASP–Arp2/3 signal was accomplished on the platform of Tks5/FISH-Grb2 complex at focal adhesions, which is stabilized by PtdIns(3,4)P2.

Abbreviations used in this paper: FA, focal adhesion; FAK, focal adhesion kinase; PH, pleckstrin homology; PX, phox homology; SH3, Src homology 3; TIRF, total internal reflection fluorescence; WASP, Wiskott-Aldrich syndrome protein.


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