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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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Osteoclasts derived from hematopoietic cells are activated on bone surface. To resorb bone, osteoclasts release acid and lysosome acid hydrolase via membrane transport. Prostate transmembrane protein ...
Phosphatase and tensin homologue deleted on chromosome ten (PTEN) regulates cell proliferation and apoptosis by inhibiting phosphatidylinositol-3 kinase (PI3K) and protein kinase (AKT) signaling. High...
To identify the upstream signaling of aluminum-induced malate secretion through aluminum-activated malate transporter 1 (AtALMT1), a pharmacological assay using inhibitors of human signal transduction...
Clinical, biochemical and molecular biology studies have identified lysosome-encapsulated cellular proteases as critical risk factors for cancer progression. Cathepsins represent a group of such prote...
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It is known that after application of MK-3475 activated PD -1 negatively regulates the activation of T cells through suppression of the path of PI3K / Akt. This study will identify the ef...
The immune response to Helicobacter pylori (Hp) importantly determines the pathogenesis of infection as well as the success of antibiotic eradication of the bacteria. The investigators wan...
This phase II trial studies how well PI3K/mTOR inhibitor LY3023414 works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with TSC or PI3K/MTOR mutati...
Segmental overgrowth disorders are rare conditions characterised by abnormal growth which is usually asymmetric and confined to discrete parts of the body. We and others have identified mo...
The purpose of this study is to determine the interaction of GLP-1 and GIP to regulate insulin secretion in nondiabetic subjects. The first part of this aim will determine the threshold pl...
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.
A cysteine protease that is highly expressed in OSTEOCLASTS and plays an essential role in BONE RESORPTION as a potent EXTRACELLULAR MATRIX-degrading enzyme.
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.
An aspartic endopeptidase that is similar in structure to CATHEPSIN D. It is found primarily in the cells of the immune system where it may play a role in processing of CELL SURFACE ANTIGENS.
A 36-amino acid peptide present in many organs and in many sympathetic noradrenergic neurons. It has vasoconstrictor and natriuretic activity and regulates local blood flow, glandular secretion, and smooth muscle activity. The peptide also stimulates feeding and drinking behavior and influences secretion of pituitary hormones.
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Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...