Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.1 (Mg2+-ATPase)
 1,484 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1-CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.
...
PMID:The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells. 2523 7

During yeast cell polarization localization of the small GTPase, cell division control protein 42 homologue (Cdc42) is clustered to ensure the formation of a single bud. Here we show that the disease-associated flippase ATPase class I type 8b member 1 (ATP8B1) enables Cdc42 clustering during enterocyte polarization. Loss of this regulation results in increased apical membrane size with scattered apical recycling endosomes and permits the formation of more than one apical domain, resembling the singularity defect observed in yeast. Mechanistically, we show that to become apically clustered, Cdc42 requires the interaction between its polybasic region and negatively charged membrane lipids provided by ATP8B1. Disturbing this interaction, either by ATP8B1 depletion or by introduction of a Cdc42 mutant defective in lipid binding, increases Cdc42 mobility and results in apical membrane enlargement. Re-establishing Cdc42 clustering, by tethering it to the apical membrane or lowering its diffusion, restores normal apical membrane size in ATP8B1-depleted cells. We therefore conclude that singularity regulation by Cdc42 is conserved between yeast and human and that this regulation is required to maintain healthy tissue architecture.
...
PMID:ATP8B1-mediated spatial organization of Cdc42 signaling maintains singularity during enterocyte polarization. 2641 59

Homeostasis of membrane phospholipids plays an important role in cell oncogenesis and cancer progression. The flippase ATPase class I type 8b member 1 (ATP8B1), one of the P4-ATPases, translocates specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. ATP8B1 is critical for maintaining the epithelium membrane stability and polarity. However, the prognostic values of ATP8B1 in colorectal cancer (CRC) patients remain unclear. We analyzed transcriptomics, genomics, and clinical data of CRC samples from The Cancer Genome Atlas (TCGA). ATP8B1 was the only potential biomarker of phospholipid transporters in CRC. Its prognostic value was also validated with the data from the Gene Expression Omnibus (GEO). Compared to the normal group, the expression of ATP8B1 was downregulated in the tumor group and the CRC cell lines, which declined with disease progression. The lower expression level of ATP8B1 was also significantly associated with worse survival outcomes in both the discovery samples (359 patients) and the validation samples (566 patients). In multivariate analyses, low ATP8B1 levels predicted unfavorable OS (adjusted HR 1.512, 95% CI: 1.069-2.137; P = 0.019) and were associated with poor progress-free interval (PFI) (adjusted HR: 1.62, 95% CI: 1.207-2.174; P = 0.001). The pathway analysis results showed that the underexpression of ATP8B1 was negatively associated with phospholipid transport, phospholipid metabolic process, and cell-cell adherent junction and positively associated with the epithelial-mesenchymal transition in CRC. Our analysis suggests that ATP8B1 is a potential cancer suppressor in CRC patients and may offer new strategies for CRC therapy.
 ...
PMID:Identification of ATP8B1 as a Tumor Suppressor Gene for Colorectal Cancer and Its Involvement in Phospholipid Homeostasis. 3306 69