title: Microtubule dynamic instability controls podosome patterning in osteoclasts through EB1, cortactin, and Src.
abstract: In osteoclasts (OCs) podosomes are organized in a belt, a feature critical for bone resorption. Although microtubules (MTs) promote the formation and stability of the belt, the MT and/or podosome molecules that mediate the interaction of the two systems are not identified. Because the growing "plus" ends of MTs point toward the podosome belt, plus-end tracking proteins (+TIPs) might regulate podosome patterning. Among the +TIPs, EB1 increased as OCs matured and was enriched in the podosome belt, and EB1-positive MTs targeted podosomes. Suppression of MT dynamic instability, displacement of EB1 from MT ends, or EB1 depletion resulted in the loss of the podosome belt. We identified cortactin as an Src-dependent interacting partner of EB1. Cortactin-deficient OCs presented a defective MT targeting to, and patterning of, podosomes and reduced bone resorption. Suppression of MT dynamic instability or EB1 depletion increased cortactin phosphorylation, decreasing its acetylation and affecting its interaction with EB1. Thus, dynamic MTs and podosomes interact to control bone resorption.
authors.affiliation: Harvard School of Dental Medicine, Department of Oral Medicine, Infection and Immunity, Boston, Massachusetts, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Biosse Duplan
authors.forename: Detina
authors.initials: D
authors.lastname: Zalli
authors.forename: Sebastien
authors.initials: S
authors.lastname: Stephens
authors.forename: Serhan
authors.initials: S
authors.lastname: Zenger
authors.forename: Lynn
authors.initials: L
authors.lastname: Neff
authors.forename: J Margit
authors.initials: JM
authors.lastname: Oelkers
authors.forename: Frank P L
authors.initials: FP
authors.lastname: Lai
authors.forename: William
authors.initials: W
authors.lastname: Horne
authors.forename: Klemens
authors.initials: K
authors.lastname: Rottner
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
mesh_terms: D000107:Acetylation; D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D021961:Cell Membrane Structures / Q000378:metabolism*; D002478:Cells, Cultured; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D051356:Cortactin; C584107:EB1 protein, mouse; D008869:Microtubule-Associated Proteins; D049452:Green Fluorescent Proteins; D019061:src-Family Kinases