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Cbl-PI3K interaction regulates Cathepsin K secretion in osteoclasts.

08:00 EDT 9th July 2019 | BioPortfolio

Summary of "Cbl-PI3K interaction regulates Cathepsin K secretion in osteoclasts."

Effective bone resorption by osteoclasts is critical for balanced bone remodeling. We have previously reported that mice harboring a substitution mutation of tyrosine 737 to phenylalanine in the adapter protein Cbl (Cbl, YF) have increased bone volume partly due to decreased osteoclast-mediated bone resorption. The Cbl mutation abrogates interaction between Cbl and the p85 subunit of PI3K. Here, we studied the mechanism for defective resorptive function of YF mutant osteoclasts. The YF osteoclasts had intact actin cytoskeletons and sealing zones. Expression and localization of proteins needed for acidification of the resorptive lacunae were also comparable between the WT and YF osteoclasts. In contrast, secretion of Cathepsin K, a major protease needed to degrade collagen, was diminished in the conditioned media derived from YF osteoclasts. The targeting of Cathepsin K into LAMP2-positive vesicles was also compromised due to decreased number of LAMP2-positive vesicles in YF osteoclasts. Further, we found that in contrast to WT, conditioned media derived from YF osteoclasts promoted increased numbers of alkaline phosphatase (ALP)-positive colonies, and increased expression of osteogenic markers in WT calvarial cultures. Cumulatively, our results suggest that the Cbl-PI3K interaction regulates Cathepsin K secretion required for proper bone resorption, and secretion of factors which promote osteogenesis.

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Name: Bone
ISSN: 1873-2763
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Medical and Biotech [MESH] Definitions

A secreted member of the TNF receptor superfamily that negatively regulates osteoclastogenesis. It is a soluble decoy receptor of RANK LIGAND that inhibits both CELL DIFFERENTIATION and function of OSTEOCLASTS by inhibiting the interaction between RANK LIGAND and RECEPTOR ACTIVATOR OF NUCLEAR FACTOR-KAPPA B.

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Phosphoinositide phosphatases that catalyze the dephosphorylation (hydrolysis) of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) to produce PtdIns(3,4)P(2), which negatively regulates the PI3K ( 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASES) pathways. They contain an SH2 DOMAIN and STERILE ALPHA MOTIF and have important functions in regulating the immune response and other cellular processes in vertebrates.

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