Tks5-dependent formation of circumferential podosomes/invadopodia mediates cell-cell fusion

J Cell Biol. 2012 May 14;197(4):553-68. doi: 10.1083/jcb.201111116.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Cell Differentiation*
  • Cell Fusion
  • Cell Line, Tumor
  • Humans
  • Mice
  • Osteoclasts / metabolism
  • Phosphate-Binding Proteins
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*


  • Adaptor Proteins, Vesicular Transport
  • Fish protein, mouse
  • Phosphate-Binding Proteins
  • Phosphoproteins
  • SH3PXD2A protein, human