Journal
JOURNAL OF CELL BIOLOGY
Volume 197, Issue 4, Pages 553-568Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201111116
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Ministry of Education, Culture, Sports, Science, and Technology [23689020]
- Takeda Science Foundation
- Keio University
- Grants-in-Aid for Scientific Research [23510254, 23689020, 23659162, 23792134] Funding Source: KAKEN
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Osteoclasts fuse to form multinucleated cells during osteoclastogenesis. This process is mediated by dynamic rearrangement of the plasma membrane and cytoskeleton, and it requires numerous factors, many of which have been identified. The underlying mechanism remains obscure, however. In this paper, we show that Tks5, a master regulator of invadopodia in cancer cells, is crucial for osteoclast fusion downstream of phosphoinositide 3-kinase and Src. Expression of Tks5 was induced during osteoclastogenesis, and prevention of this induction impaired both the formation of circumferential podosomes and osteoclast fusion without affecting cell differentiation. Tyrosine phosphorylation of Tks5 was attenuated in Src(-/-) osteoclasts, likely accounting for defects in podosome organization and multinucleation in these cells. Circumferential invadopodia formation in B16F0 melanoma cells was also accompanied by Tks5 phosphorylation. Co-culture of B16F0 cells with osteoclasts in an inflammatory milieu promoted the formation of melanoma-osteoclast hybrid cells. Our results thus reveal an unexpected link between circumferential podosome/invadopodium formation and cell-cell fusion in and beyond osteoclasts.
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