title: BAR Proteins PSTPIP1/2 Regulate Podosome Dynamics and the Resorption Activity of Osteoclasts.
abstract: Bone resorption in vertebrates relies on the ability of osteoclasts to assemble F-actin-rich podosomes that condense into podosomal belts, forming sealing zones. Sealing zones segregate bone-facing ruffled membranes from other membrane domains, and disassemble when osteoclasts migrate to new areas. How podosome/sealing zone dynamics is regulated remains unknown. We illustrate the essential role of the membrane scaffolding F-BAR-Proline-Serine-Threonine Phosphatase Interacting Proteins (PSTPIP) 1 and 2 in this process. Whereas PSTPIP2 regulates podosome assembly, PSTPIP1 regulates their disassembly. PSTPIP1 recruits, through its F-BAR domain, the protein tyrosine phosphatase non-receptor type 6 (PTPN6) that de-phosphophorylates the phosphatidylinositol 5-phosphatases SHIP1/2 bound to the SH3 domain of PSTPIP1. Depletion of any component of this complex prevents sealing zone disassembly and increases osteoclast activity. Thus, our results illustrate the importance of BAR domain proteins in podosome structure and dynamics, and identify a new PSTPIP1/PTPN6/SHIP1/2-dependent negative feedback mechanism that counterbalances Src and PI(3,4,5)P3 signalling to control osteoclast cell polarity and activity during bone resorption.
authors.affiliation: Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307, Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Sztacho
authors.affiliation: Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307, Dresden, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Segeletz
authors.affiliation: Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307, Dresden, Germany.
authors.forename: Maria Arantzazu
authors.initials: MA
authors.lastname: Sanchez-Fernandez
authors.affiliation: Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307, Dresden, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Czupalla
authors.affiliation: Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307, Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Niehage
authors.affiliation: Biotechnology Center, Technische Universität Dresden, Tatzberg 47-51, 01307, Dresden, Germany.
authors.forename: Bernard
authors.initials: B
authors.lastname: Hoflack
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000378:metabolism; D000069261:Podosomes / Q000378:metabolism*; D000072417:Protein Domains; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism; D040901:Proteomics; D000067996:RAW 264.7 Cells; D034622:RNA Interference
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C110097:Pstpip1 protein, mouse; C486383:Pstpip2 protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C000606433:Inpp5d protein, mouse; C000606435:Inppl1 protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases