title: Involvement of the Src-cortactin pathway in podosome formation and turnover during polarization of cultured osteoclasts.
abstract: Osteoclasts are large, multinucleated cells that adhere to bone via podosomes, and degrade it. During osteoclast polarization, podosomes undergo reorganization from a scattered distribution, through the formation of clusters and ring super-structures, to the assembly of a sealing zone at the cell periphery. In the present study, we demonstrate that the levels of podosome-associated actin, and its reorganization in cultured osteoclasts, radically increase upon formation of podosome rings. At the peripheral ring, actin levels and dynamic reorganization were high, whereas paxillin, associated with the same adhesion super-structure, remained relatively stable. These dynamic changes were regulated by the tyrosine kinase pp60c-Src, whose scaffolding activity supported the assembly of immature stationary podosomes; its catalytic activity was essential for podosome maturation and turnover. The enhanced dynamic reorganization of podosomes during osteoclast polarization was inversely related to the local levels of tyrosine phosphorylation of the Src substrate, cortactin. Furthermore, overexpression of cortactin, mutated at its major Src phosphorylation sites, enhanced actin turnover, suggesting that podosome dynamics in polarizing osteoclasts are attributable to the downregulation of cortactin activity by its Src-dependent phosphorylation.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Luxenburg
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Parsons
authors.forename: Lia
authors.initials: L
authors.lastname: Addadi
authors.forename: Benjamin
authors.initials: B
authors.lastname: Geiger
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000502:physiology*; D002478:Cells, Cultured; D051356:Cortactin / Q000502:physiology*; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D051356:Cortactin; C495869:Cttn protein, mouse; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)