title: p130Cas, Crk-associated substrate, plays important roles in osteoclastic bone resorption.
abstract: p130Cas, Crk-associated substrate (Cas), is an adaptor/scaffold protein that plays a central role in actin cytoskeletal reorganization. We previously reported that p130Cas is not tyrosine-phosphorylated in osteoclasts derived from Src-deficient mice, which are congenitally osteopetrotic, suggesting that p130Cas serves as a downstream molecule of c-Src and is involved in osteoclastic bone resorption. However, the physiological role of p130Cas in osteoclasts has not yet been confirmed because the p130Cas-deficient mice displayed embryonic lethality. Osteoclast-specific p130Cas conditional knockout (p130Cas(ΔOCL-) ) mice exhibit a high bone mass phenotype caused by defect in multinucleation and cytoskeleton organization causing bone resorption deficiency. Bone marrow cells from p130Cas(ΔOCL-) mice were able to differentiate into osteoclasts and wild-type cells in vitro. However, osteoclasts from p130Cas(ΔOCL-) mice failed to form actin rings and resorb pits on dentine slices. Although the initial events of osteoclast attachment, such as β3-integrin or Src phosphorylation, were intact, the Rac1 activity that organizes the actin cytoskeleton was reduced, and its distribution was disrupted in p130Cas(ΔOCL-) osteoclasts. Dedicator of cytokinesis 5 (Dock5), a Rho family guanine nucleotide exchanger, failed to associate with Src or Pyk2 in osteoclasts in the absence of p130Cas. These results strongly indicate that p130Cas plays pivotal roles in osteoclastic bone resorption.
authors.affiliation: Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Fukuoka, Japan; Division of Developmental Stomatognathic Function Science, Department of Health Improvement, Kyushu Dental University, Fukuoka, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Nagai
authors.forename: Kenji
authors.initials: K
authors.lastname: Osawa
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Tamura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aoki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohya
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.forename: Hisako
authors.initials: H
authors.lastname: Hikiji
authors.forename: Mariko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Seta
authors.forename: Sachiko
authors.initials: S
authors.lastname: Seo
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakamura
authors.forename: Kenshi
authors.initials: K
authors.lastname: Maki
authors.forename: Eijiro
authors.initials: E
authors.lastname: Jimi
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002454:Cell Differentiation; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D010012:Osteogenesis; D010641:Phenotype; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D050719:Crk-Associated Substrate Protein; C531318:Dock5 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; D020830:rac1 GTP-Binding Protein
keywords: ACTIN CYTOSKELETON; BONE RESORPTION; OSTEOCLASTS; p130CAS