Oikawa et al. describe how the adaptor protein Tks5 promotes the formation of invasive podosomes in order to induce osteoclast cell fusion.
As precursor cells differentiate into bone-resorbing osteoclasts, they assemble rings of actin-rich membrane protrusions called podosomes. The precursors then fuse with each other to form giant, multinucleate osteoclasts that seal to the surface of bones through a stable podosome belt. How osteoclast precursors fuse is unknown, but Oikawa et al. saw that fusion occurred at sites where protrusions from one cell's podosome ring extended into a neighboring cell.
These podosome-associated protrusions contained the phospholipids PtdIns(3,4)P2 and PtdIns(3,4,5)P3, as well as the phospholipid-binding adaptor protein Tks5, which promotes the formation of invasive protrusions called invadopodia in cancer cells. Osteoclast precursors lacking Tks5 formed fewer podosomes and failed to fuse with each other. Podosome assembly and cell fusion was rescued by wild-type Tks5 but not by a mutant lacking the protein's phospholipid-binding domain. In addition, Tks5 was phosphorylated by the tyrosine kinase Src, and a phosphomimetic mutant of Tks5 partially rescued the podosome organization and fusion defects seen in Src-null osteclasts.
Src and phospholipid binding may therefore activate Tks5 to stimulate podosome-based protrusions that destabilize the plasma membrane of neighboring cells to induce osteoclast fusion. Tks5 also promoted the fusion of osteoclasts with melanoma cells to produce a type of hybrid cell found in cancer patients. Author Tsukasa Oikawa now wants to investigate how such hybrid cells contribute to bone metastasis.