Disease relevance of Atp6v0d2

• Our results further indicate that blocking the expression of CA II and V-ATPase with antisense RNA or DNA leads to decreased bone resorption [1].
• The results suggest that the inhibition of V-ATPase function via knockdown of ATP6L expression using RNA interfering technology can effectively retard the cancer growth and suppress the cancer metastasis by the decrease of proton extrusion and the down-regulation of gelatinase activity [2].
• Introduction: The TCIRG1 gene encodes the a3 isoform of the V-ATPase a subunit, and mutations at this locus account for approximately 60% of infantile malignant osteopetrosis cases [3].
• Although these anticancer effects of bafilomycin are considered to be attributable to the intracellular acidosis by V-ATPase inhibition, the exact mechanism remains unclear [4].
• Bafilomycin A1, a macrolide antibiotic isolated from Streptomyces species, has been used as an inhibitor of vacuolar H(+) ATPase (V-ATPase) [4].

High impact information on Atp6v0d2

• In osteoclast cultures treated with the 16-kD V-ATPase antisense RNA, acidification of an unknown population of intracellular vesicles was highly stimulated [1].
• Instead, the E5-induced pH differential was attributed to impairment of V-ATPase activity, even though the amount of ATPase present in the Golgi complex was unaltered [5].
• Since E5 also interacts with the 16-kD pore-forming subunit of the vacuolar H(+)-ATPase (V-ATPase), the oncoprotein could conceivably interfere with the pH homeostasis of the Golgi complex [5].
• While the precise mechanism of receptor activation is unknown, E5 associates with several cellular proteins, including PDGF-R and the 16K V-ATPase protein, and induces the preferential phosphorylation of immature, Endo H-sensitive forms of the receptor [6].
• Cn and V-ATPase modulate effector gene expression at the mRNA level by inhibiting transcription factor NF-kappaB [7].

Chemical compound and disease context of Atp6v0d2

• Specific inhibitors of vacuolar H(+)-ATPase (V-ATPase), concanamycin A and bafilomycin A1, abolish bone resorption by osteoclasts [8].
• An acidic microenvironment, which is formed by vacuolar adenosine 5'-triphosphatase (V-ATPase) expressed in the plasma membranes of osteoclasts, is indispensable for osteoclastic bone resorption [9].

Biological context of Atp6v0d2

• Comparison of the kinetic properties of V-ATPase complexes containing Vma6p and d1 demonstrate that although the Km for ATP hydrolysis is similar (0.26 and 0.31 mm, respectively), the coupling ratio (proton transport/ATP hydrolysis) is approximately 3-6-fold higher for d1-containing complexes than for Vma6p-containing complexes [10].
• In situ hybridization showed that NM9.2 gene expression was restricted mainly to neuronal cells and consistent with that of the a1/Ac116 subunit of V-ATPase [11].
• Sequence analysis revealed that NM9.2 conserved similar characteristic amino acid sequences with 60-70% identity to M9.2 previously isolated from V-ATPase in chromaffin granules [11].
• Although the G3 and d2 did not rescue the vmaDelta phenotype, d1 and the two C isoforms functionally complemented the Deltavma6 and Deltavma5, respectively, indicating that they are bona fide subunits of V-ATPase [12].
• Here we show that both the B1 (kidney) and B2 (brain) isoforms of the B subunit of V-ATPase contain a microfilament binding site in their amino-terminal domain [13].

Anatomical context of Atp6v0d2

• Interestingly, XS52 DC expressed seven-fold higher V-ATPase proton-pump activity than J774 macrophages and distinguished from the macrophage by high levels of isoforms a1 and a2 expression among V-ATPase subunits [14].
• The negative effects of V-ATPase and Cn on NF-kappaB-dependent gene expression are not limited to the macrophage lineage, as similar effects have been seen with a murine fibroblast cell line and with primary astrocytes [7].
• Local extracellular acidification is carried out by vacuolar type H+-ATPase (V-ATPase) localized in the plasma membrane [15].
• The vacuolar-type H+ -ATPase (V-ATPase) translocates protons across membranes [16].
• Vacuolar H(+)-ATPase (V-ATPase) binds microfilaments, and that interaction may be mediated by an actin binding domain in subunit B of the enzyme [17].

Associations of Atp6v0d2 with chemical compounds

• Here, we reported the molecular cloning and characterization of three novel subunit isoforms, C2, d2 and G3, of mouse V-ATPase [12].
• V-ATPase, which overly functions in some cancers with metastatic potential, plays an important role in maintaining neutral cytosolic pH, very acidic luminal pH, and acidic extracellular pH [2].
• To test for possible physiologic functions of the actin binding activity of V-ATPase, early responses of resorbing osteoclasts to inhibition of phosphatidylinositol 3-kinase activity by wortmannin and LY294002 were examined [17].
• Unique cysteine residues were introduced into a Cys-less form of subunit B, and the V-ATPase complex in isolated vacuolar membranes from each mutant strain was reacted with the bifunctional, photoactivable maleimide reagent 4-(N-maleimido)benzophenone [18].
• The direct binding interaction between V-ATPase and aldolase may be a new mechanism for the regulation of the V-ATPase and may underlie the proximal tubule acidification defect in hereditary fructose intolerance [19].

Physical interactions of Atp6v0d2

• V-ATPase in osteoclasts cultured in vitro was found to form a detergent-insoluble complex with actin and myosin II through direct binding of V-ATPase to actin filaments [20].

Co-localisations of Atp6v0d2

• In immunocytochemical assays, aldolase was found to colocalize with V-ATPase in the renal proximal tubule [19].
• After stimulation, the V-ATPase with the a3 isoform was immunochemically colocalized with lysosome marker lamp2 and was detected in acidic organelles [15].
• In contrast, Rab11 colocalized with V-ATPase in apical regions of proximal tubule, and Rab20 colocalized with the enzyme in intercalated cells [21].

Regulatory relationships of Atp6v0d2

• CONCLUSIONS: The immunohistochemical data in combination with the membrane fractionation studies are consistent with a potential role for Rab11 and Rab20 in regulating V-ATPase traffic in specific segments of the nephron [21].
• Immunopurified V-ATPase from 1,25(OH)2D3-stimulated cultures exhibited 20-fold greater ATPase activity than the enzyme from unstimulated cultures, which do not contain osteoclasts [22].

Other interactions of Atp6v0d2

• NM9.2 is a putative neuronal isoform of the 9.2 kDa subunit in V-ATPase [11].
• A novel putative M9.2 isoform of V-ATPase expressed in the nervous system [11].
• A putative role of Ac39/physophilin in the inactivation of the V-ATPase by disassembly of its V1 sector is also discussed [23].
• Ac39 has recently been shown to be present in a synaptosomal complex which, in addition to synaptophysin, includes the bulk of synaptobrevin II, and subunits c and Ac115 of the V0 sector of the V-ATPase [23].
• These results suggest that the V-ATPase, with the a4 isoform, is important for renal acid/base homeostasis [16].

Analytical, diagnostic and therapeutic context of Atp6v0d2

• Immunoprecipitation experiments, together with sequence similarities for other isoforms (a1, a2, and a3), indicate that the a4 isoform is a component of V-ATPase [16].
• Immunohistochemistry with isoform-specific antibodies revealed that V-ATPase with C2-a is localized specifically in lamellar bodies of type II alveolar cells, whereas the C2-b isoform is found in the plasma membranes of renal alpha and beta intercalated cells [24].
• Rapid co-localization between V-ATPase and F-actin was demonstrated by immunocytochemistry, and corresponding association between V-ATPase and F-actin in immunoprecipitations and pelleting assays was detected [17].
• The interaction between V-ATPase E and Sos-DH was confirmed by yeast two-hybrid assay [25].
• We have employed a combination of site-directed mutagenesis and covalent cross-linking to identify subunits in close proximity to subunit B in the vacuolar H(+)-ATPase (V-ATPase) complex [18].

References