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J. Biol. Chem., Vol. 276, Issue 50, 47434-47444, December 14, 2001
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From the Podosomes are adhesion structures in osteoclasts
and are structurally related to focal adhesions mediating cell motility
during bone resorption. Here we show that gelsolin coprecipitates some of the focal adhesion-associated proteins such as c-Src,
phosphoinositide 3-kinase (PI3K), p130Cas, focal
adhesion kinase, integrin
Phosphatidylinositol 3,4,5-Trisphosphate Directs Association
of Src Homology 2-containing Signaling Proteins with
Gelsolin*
§,,, Department of Oral and Craniofacial
Biological Sciences, University of Maryland, Baltimore, Maryland 21201 and ¶ Department of Pediatrics, Washington University School of
Medicine, St. Louis, Missouri 63110
v
3, vinculin,
talin, and paxillin. These proteins were inducibly
tyrosine-phosphorylated in response to integrin activation by
osteopontin. Previous studies have defined unique biochemical
properties of gelsolin related to phosphatidylinositol 3,4,5-trisphosphate in osteoclast podosomes, and here we demonstrate phosphatidylinositol 3,4,5-trisphosphate/gelsolin function in mediating organization of the podosome signaling complex. Overlay and
GST pull-down assays demonstrated strong phosphatidylinositol 3,4,5-trisphosphate-PI3K interactions based on the Src homology 2 domains of PI3K. Furthermore, lipid extraction of lysates from activated osteoclasts eliminated interaction between gelsolin, c-Src,
PI3K, and focal adhesion kinase despite equal amounts of gelsolin in
both the lipid-extracted and unextracted experiment. The cytoplasmic
protein tyrosine phosphatase (PTP)-proline-glutamic acid-serine-threonine amino acid sequences (PEST) was also found to be associated with gelsolin in osteoclast podosomes and with stimulation of v3-regulated
phosphorylation of PTP-PEST. We conclude that gelsolin plays a key role
in recruitment of signaling proteins to the plasma membrane
through phospholipid-protein interactions and by regulation of their
phosphorylation status through its association with PTP-PEST. Because
both gelsolin deficiency and PI3K inhibition impair bone resorption, we
conclude that phosphatidylinositol 3,4,5-trisphosphate-based protein
interactions are critical for osteoclast function.
*
This work was supported by National Institutes of Health
Grants AR46292 (to M. A. C.), AR41677 (to K. A. H.), DK09976 (to K. A. H.) and by a grant (DRIF) from the University of Maryland Dental
School, Baltimore, MD.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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