Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-/-) mice.
The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2(-/-) mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions.
Gil-Henn
Hava
H
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06511, USA.
Destaing
Olivier
O
Sims
Natalie A
NA
Aoki
Kazuhiro
K
Alles
Neil
N
Neff
Lynn
L
Sanjay
Archana
A
Bruzzaniti
Angela
A
De Camilli
Pietro
P
Baron
Roland
R
Schlessinger
Joseph
J
D000818:Animals; D015519:Bone Density / Q000502:physiology*; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism / Q000648:ultrastructure*; D010022:Osteopetrosis / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D020741:rho GTP-Binding Proteins