RRC ID 12035
Author Yogo K, Mizutamari M, Mishima K, Takenouchi H, Ishida-Kitagawa N, Sasaki T, Takeya T.
Title Src homology 2 (SH2)-containing 5'-inositol phosphatase localizes to podosomes, and the SH2 domain is implicated in the attenuation of bone resorption in osteoclasts.
Journal Endocrinology
Abstract c-Src plays an important role in bone resorption by osteoclasts. Here, we show using wild-type and ship(-/-) osteoclasts that Src homology 2 (SH2)-containing 5'-inositol phosphatase (SHIP) appeared to negatively regulate bone resorption activated by c-Src. SHIP was found to localize to podosomes under the influence of c-Src, and the presence of either the amino-terminal region comprising the SH2 domain or the carboxyl-terminal region was sufficient for its localization. Although SHIP lacking a functional SH2 domain was still found in podosomes, it could not rescue the hyper-bone resorbing activity and hypersensitivity to receptor activator of nuclear factor-kappaB ligand in ship(-/-) osteoclasts, suggesting that the localization of SHIP to podosomes per se was not sufficient and the SH2 domain was indispensable for its function. Cas and c-Cbl, known to function in podosomes of osteoclasts, were identified as novel proteins binding to the SHIP SH2 domain by mass spectrometric analysis, and this interaction appeared to be dependent on the Src kinase activity. These results demonstrate that c-Src enhances the translocation of SHIP to podosomes and regulates its function there through the SH2 domain, leading to an attenuation of bone resorption.
Volume 147(7)
Pages 3307-17
Published 2006-7-1
DOI 10.1210/en.2005-1309
PII en.2005-1309
PMID 16601135
MeSH Animals Bone Resorption* Cell Line Inositol Polyphosphate 5-Phosphatases Mass Spectrometry Mice NF-kappa B / metabolism NIH 3T3 Cells Osteoclasts / enzymology Osteoclasts / metabolism* Phosphatidylinositols / metabolism Phosphoric Monoester Hydrolases / metabolism* Phosphoric Monoester Hydrolases / physiology* Protein Binding Protein Transport Proto-Oncogene Proteins pp60(c-src) / chemistry* src Homology Domains*
IF 3.934
Times Cited 20
DNA material pCAhMCSF Human M-CSF (RDB1524)