Database for Annotation, Visualization and Integrated Discovery 2.1
National Institute of Allergy and Infectious Disease
The Database for Annotation, Visualization and Integrated Discovery
DAVID Functional Annotation Table
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solute carrier family 9 member A1(SLC9A1) solute carrier family 9 member A1(SLC9A1) Related Genes Homo sapiens
CYTOBAND 1p36.1-p35,
GENERIF_SUMMARY Anion exchanger isoform 2 operates in parallel with Na(+)/H(+) exchanger isoform 1 during regulatory cell volume decrease., Data indicate for the first time that two acid extruders, Na(+)-H(+) exchanger and Na(+)-HCO(3)(-) symporter, exist functionally and pH(i) dependently in human atrial cardiomyocytes., serum-independent activation of NHE1 by bound CHP2 is one of the key mechanisms for the maintenance of high pH(i) and the resistance to serum deprivation-induced cell death in malignantly transformed cells, MCT1 and NHE1 genes play important regulation roles in proliferation and growth of tumor cells, probably by affecting pHi., both Arg(440) in IL5 and Gly residues in the conserved segment of TM11 appear to constitute important elements for proper functioning of the putative "pH(i) sensor" of Na(+)/H(+) exchanger 1., Regulation of placental NHE-1 not due to differences in C-terminus structure. Suppression regulated post-transcriptionally. Change in NHE-1 may contribute to adequate provision of electrolytes and nutrients to fetus., identification in human reticulocytes and erythrocytes of an alternative splicing of NHE lacking the amiloride binding site, Both Pro167 and Pro168 are strictly required for NHE function and may play critical roles in the structure of transmembrane segment IV of the NHE., Association of NHE1 with calcineurin B homologous protein (CHP) is crucial for maintenance of the pH(i) sensitivity of NHE1; tightly bound Ca2+ ions may serve as important structural elements in the pHi sensor of NHE1., NHE1 promotes cell survival by dual mechanisms, Children with higher baseline Na-Li countertransporter(CT) had greater blood pressure change than children in lower baseline Na-Li CT and were associated with greater risk of high blood pressure compared to lower Na-Li CT., Results describe the topogenesis of a hydrophobic lumenal loop segment between transmembrane segments 9 and 10 of human sodium/hydrogen exchanger isoform 1., The relative fluorescence density of NHE-1 is significantly higher in isolated liver nuclei of human, when compared with those of rabbit and rat., The antagonistic roles of RhoA and Rac1 in cell motility/invasion and cytoskeletal organization in breast cancer may be due to their concerted action on NHE1 activity as a convergence point., acidic aa sequence is critical in proper conformation of the cytosolic domain, calmodulin binding, and in activity, Transmembrane (TM) segment IV of Na+/H+ exchanger isoform 1 (NHE1) is an unusually structured TM segment exquisitely sensitive to mutagenesis and Phe161 is a pore-lining residue., NHE activity in the microvillus of syncytiotrophoblasts is attributable predominantly to NHE1., The results suggest that PP1 is an important regulatory phosphatase of NHE1, that it can bind to and dephosphorylate the protein, and that it regulates NHE1 activity in vivo., a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module is regulated by Protein Kinase A gating and then regulates invasion in breast cancer cell lines, Data show that the Na+/H+ exchanger (NHE), NHE1, is functionally active in HEK 293 cells, and resides in lipid rafts or caveolae, which may create cellular microdomains where pH(i) is tightly regulated., In conclusion, EGF protects esophageal epithelial cells against acid through NHE activation via Ca(2+)/calmodulin and the PKC pathway., carbonic anhydrase II binds to the penultimate group of 13 amino acids of the cytoplasmic tail of NHE1. a novel phosphorylation-regulated CAII binding site exists in distal amino acids of the NHE1 tail., crystallographic analysis of the human calcineurin homologous protein CHP2 bound to the cytoplasmic region of the Na+/H+ exchanger NHE1, These findings suggest that CHP serves as an obligatory subunit that is required both for supporting the basic activity and regulating the pH-sensing of NHE1 via interactions between distinct parts of these proteins [CHP2]., TM VII is a critical transmembrane segment structured as an interrupted helix, with several residues that are essential to both protein function and sensitivity to inhibition., helix formation of the cytoplasmic region of NHE1 by calcineurin B homologous protein 1 is a prerequisite for generating the active form of NHE1, data support the view that dimerization of two active subunits are required for NHE1 to possess the exchange activity in the neutral pH(i) range, the existence of a positive feedback loop between NHE1 and ERK can pose a barrier against apoptosis., Both intact Ser(770) and Ser(771) were required for sustained acidosis-mediated activation of NHE1, The NHERF1 PDZ2 domain regulates PKA-RhoA-p38-mediated NHE1 activation and invasion in breast tumor cells., Review. The role of NHE-1 hyperactivity in cardiac overload, ischemia/reperfusion injury, and myocardial hypertrophy is discussed., Vpr-mediated NHE1 dyregulation is in part through GR pathway, We highlight evidence for the nontransport functions of NHE1 and describe how the structural functions are integrated with ion translocation to regulate a range of cellular processes[review], Results support the view that the multiple charged residues identified in this study, along with several basic residues reported previously, participate in the regulation of the intracellular pH sensing of Na+/H+ exchanger 1., Epidermal growth factor upregulates NHE1 by post-translational regulation that is important for cervical cancer cell invasiveness., These data provide the first evidence that both EGF and S1P stimulate NHE activity in the syncytiotrophoblast; they appear to do so predominantly by activating the NHE1 isoform., NHE1 activity generates a proton gradient at the cell surface accompanied by the cells' ability to respond to changes in pH in melanoma, T84 human colon cells contain three isoforms of the Na+/H+ exchanger, NHE1, NHE2, and NHE4, but not the Cl-dependent NHE, Model structure of the Na+/H+ exchanger 1 in human and E. coli, Three MAPKs exhibit unique interrelationships with the Na(+)/H(+) exchanger, NHE1, after osmotic cell shrinkage, Data support a novel molecular function of Daxx as an upstream regulator of NHE1 in ischemic cell death., after the 4-wk sprint training period, the expression of the muscle Na+-K+ pump alpha1-subunit and Na+/H+-exchanger isoform 1 was higher, These observations suggest that Na(+)/H(+) exchange plays a permissive role in cell motility but is not required for the initiation or development of the migratory response., NHE1 regulates Ca(2+) signaling via the modulation of Ca(2+) release from the endoplasmic reticulum, contributing to the regulation of proliferation in brain pericytes., Data suggest that localization of NHE-1 in membrane cholesterol- and caveolin-rich microdomains constitutes a novel physiological negative regulator of NHE-1 activity., NHE1 has a role in restraining the malignant behavior of human gastric carcinoma cells, critical for countering renal tubular atrophy and chronic renal disease progression, Enhanced activity of the cardiac Na+/H+ exchanger (NHE-1) after myocardial stretch is considered a key step of the signaling pathway leading to cardiac hypertrophy[REVIEW]., The structure of a peptide representing amino acids 338-365 of NHE1 determined by using high resolution NMR in dodecylphosphocholine micelles showed two helical regions kinked with a large bend angle around a pivot point at amino acid Ser(351), These findings jklconfirm a necessary function for NHE1 during apoptosis and reveal the critical regulatory sites that mediate the alkalinizing activity of NHE1 in the early stages of a cell death response., Protein kinase B/Akt phosphorylates and inhibits the cardiac Na+/H+ exchanger NHE1., Activation of NHE1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure., HPV16 E7-dependent transformation activates NHE1 through a PKA-RhoA-induced inhibition of p38alpha., Membrane targeting and coupling of NHE1-integrinalphaIIbbeta3-NCX1 by lipid rafts following integrin-ligand interactions trigger Ca2+ oscillations., analysis of transmembrane XI of the NHE1 isoform of the Na+/H+ exchanger, Inhibition of the Na+-H+ exchanger isoform 1 (NHE1) also inhibited leptin-induced superoxide anion production but at the same time amplified leptin-induced production of other oxidative species, The functional and molecular expression of NHEs in cultured human endolymphatic sac (ES) epithelial cells was determined and the effect of IFN-gamma on NHE function, was examined., Results predict that other functions shared by Akt and NHE1, including cell growth and survival, might be regulated by increased H(+) efflux., Structural and functional analysis of extracellular loop 2 of the Na(+)/H(+) exchanger., Over-expression of Na+/H+ exchanger 1 is associated with hepatocellular carcinoma., These data provide evidence for tumor-selective downregulation of NHE1 by activated PPARgamma, results suggest that both NHE1 and MnSOD have peroxisome proliferator response elements binding motif in their upstream/promoter region and hence are regulated by PPAR upon ligand binding., neurotensin /NTR1 signaling in pancreatic cancer cells seems to promote the induction of a metastatic phenotype, in contrast to its varying effects on tumor cell proliferation., NHE1 plays a role in hepatocellular carcinoma (HCC) invasion and that NHE1 may be a potential therapeutic target for HCC treatment., Results suggest that the association of NHE-1 with Na-K-ATPase is critical for ouabain-mediated regulation of Na-K-ATPase and that these effects may play a role in cardioglycoside-stimulated hypertension., NHE1 is a potential target in breast cancer and in spite of their similar transport functions, NHE1 and NBCn1 serve different functions in MCF-7 cells, data show a concordance among NHE1 localization, the generation of a well-defined acidic extracellular pH in the nanospace surrounding invadopodia, and matrix-degrading activity at invadopodia of human malignant breast carcinoma cells, The expression of NHE1 is up-regulated during apoptosis of HL-60 cells induced by etoposide., The AMP-dependent kinase AMPK is a powerful regulator of NHE1 activity and thus contributes to the regulation of cytosolic pH (pHi) and pHi-dependent metabolic pathways., The expression levels of NHE1 mRNA and protein are significantly up-regulated in gastric carcinoma tissue., Nedd4-1 and beta-arrestin-1 as key regulators of NHE1 ubiquitylation, endocytosis, and function., a structural model of the transmembrane part of hNHE1, This review focuses on the contribution of NHE-1 in atherogenesis and considers the relationship between NHE-1 and vascular risk factors of certain diseases, including hypertension and inflammation., The calmodulin binding site A of hNHE1 protein is responcible for the stimulation with angiotensin II, the calmodulin binding site B is important to maintain its basal activity., Intracellular pH gradients established by NHE1 activity exist along the axis of cell movement., Na(V)1.5 and NHE1 are functionally coupled and enhance the invasiveness of cancer cells by increasing H(+) efflux., NHE1 might participate in HIF-1-induced angiogenesis due, at least in part, to the alteration of calpain activity., These findings suggest that NHE-1 in ulcerative colitis is regulated by NFkB induced through TLR-4 and MyD88 signaling mechanism., NHE1 was overexpressed in hepatocellular carcinoma (HCC) and that inhibition of NHE1 could be a potential therapeutic target for HCC., B-Raf associates with and stimulates NHE1 activity and that B-Raf(V600E) also increases NHE1 activity that raises intracellular pH., This review of role of NHE1 in pathogenesis of lactic acidosis causing kidney dysfunction focuses on the benefits of NHE1 transporter inhibition., In mineralizing osteoblasts, slightly basic basal intracellular pH is maintained, and external acid load is dissipated, by high-capacity Na(+) /H(+) exchange via NHE1 and NHE6., That normal NHE1 function depends on a protein recognition element within the ID region that may be linked to NHE1 trafficking via an acidic ER export motif., Silencing the NHE1 gene significantly inhibited the hypoxia-induced proliferation, hypertrophy, and migration of human pulmonary artery smooth muscle cells via repression of the nuclear transcription factor E2F1., The NHE1 mediates MDA-MB-231 cells invasion partly through regulating MT1-MMP in ERK1/2 and p38 MAPK signaling pathways dependent manner., inhibition of NHE1 activity can promote hypoxia-induced K562 cell differentiation, Expression of NHE1 is up-regulated during apoptosis of HL-60 cells. Expression was not up-regulated in K562 cells., molecular mechanisms of the phosphorylation-dependent regulation of NHE1, NHE1 mediates HeLa cell metastasis via regulating the expression and localization of MT1-MMP and provides a theoretical basis for the development of novel therapeutic strategies targeting cervical cancer., Data show that DeltaNErbB2 expression elicited Na(+), HCO(3)(-) cotransporter NBCn1 upregulation, Ser(703)-phosphorylation of Na(+)/H(+) exchanger NHE1., results indicate that NHE1 is necessary for IGF-II-induced proliferation response of human gastric myofibroblasts, Inhibition or shRNA-based depletion of the Na(+)/H(+) exchanger NHE-1, along with intracellular pH monitoring by live-cell imaging, revealed that invadopodia formation is associated with alterations in cellular pH homeostasis, a novel function for NHE1 and NCX1 in membrane blebbing and permeability, and establish a link between membrane blebbing and integrin signaling., Increased apical Na/H exchanger activity correlates with increased apical NHE1 expression in mutant cells, and increased apical localization in collecting ducts of kidney sections from transgenic polycystic kidney disease mice compared with control mice., NHE1 plays a critical role in the hypoxia-induced differentiation of K562 cells by regulating C/EBPa gene expression via activation of p38 MAPK signalling pathway., NHE1 directly binds to calcineurin A and activates downstream NFAT signaling, leading to cardiomyocyte hypertrophy, NHE-1 on 1p is silenced in oligodendrogliomas secondary to IDH-associated hypermethylation and 1p allelic loss., results suggest that EL4 makes an extension upward from TM VII to make up part of the mouth of the NHE1 protein and is involved in cation selectivity or coordination, Extracellular acidosis induces Ca(2+) oscillation via NHE1, leading to Ca(2+)/CaMKII-dependent CREB activation in human central nervous system pericytes., Loss of both N-myristoylation and calcium binding of CHP3 decreases cell surface stability of NHE1., Report that NHE1 generates measurable pH nanodomains right at focal adhesions in melanoma cells., Functional insights inferred from NHE1 structure models and analysis. [Review], NHE-1 is important for microglial (macrophage) activation and participates in the inflammatory response under pathological conditions including cerebral ischemia and traumatic brain injury., novel role of STCH in the regulation of pHi through site-specific interactions with NBCe1-B and NHE1 and subsequent modulation of membrane transporter expression., NHE1 is a new ATP-binding transporter that belongs to a major facilitator superfamily., Studies indicate that the activity of Na+/H+ Exchanger (NHE1) is regulated through the phosphorylation of key amino acids in the cytosolic domain as well as by its interaction with other intracellular proteins and lipids., The molecular mechanisms underlying NHE1 regulation. [Review], NHE1 mediated contributions to myocardial injury may be attenuated by pharmacological inhibition. [Review], Phosphorylation of S770/S771 changes the conformation of the NHE1 C-terminal regulatory region in a pH-dependent manner., NHE1 appears to be the only significant regulator of intracellular pH in preimplantation mouse embryos., acute acidosis activates NHE1 in mammalian kidney cells, Disruption of the DNM2-dependent retrograde trafficking of NHE1 contributes to cardiomyocyte apoptosis., NaV1.5 colocalises with NHE-1 and caveolin-1 at the sites of matrix remodelling in invadopodia., NHE1 and calmodulin associate in vivo through endothelin-dependent cytosolic signaling pathways., modulation of NHE1 activity by various activators and inhibitors occurs through the direct binding of these molecules to the LID, which alters the association of the LID with the plasma membrane., Protease activity suppression increases relative invadopodial NHE1 expression, while NHE1 inhibition increases acid-induced protease secretion., The regulation of NHE-1 activity mediated by PKC-beta activation involves NHE-1 phosphorylation, which implies that the phosphorylation of NHE-1 directly affects glutamate-induced neuronal cell death., CD44 regulates the metastasis of breast cancer cells through regulating NHE1 expression, which could be used as a novel strategy for breast cancer therapy., probucol via inhibition of NHE1 attenuates atherosclerosis lesion growth and promotes plaque stability, NHE1 upregulation is an important cytoprotective mechanism in human glioma cells., NHE1 transmembrane (TM) region VI from V240 to V245 is closely associated with TM region VII and, in agreement with nuclear magnetic resonance (NMR) structure of VI-VII segments, V242 and F260 are in close association., Talin has a role in regulating moesin-NHE-1 recruitment to invadopodia in breast cancer, CIAPIN1 targeted NHE1 to mediate differentiation of K562 cells via ERK1/2 pathway., The results demonstrate that the Ser771Pro human genetic mutation has significant and detrimental physiological effects on the activity of the NHE1 protein, SLC9A1., Concurrent speed endurance and resistance training increases skeletal muscle NHE1 activity., Mutation of SLC9A1 is associated with ataxia-deafness Lichtenstein-Knorr syndrome., We demonstrate, for the first time, that 3 different pHi regulators responsible for acid extruding, i.e. NHE and NBC, and MCT, are functionally co-existed in cultured radial artery smooth muscle cells., These results suggest a novel tumor suppressor function of merlin in melanoma cells, The findings are consistent with a role for R425 in both neutralizing a helix dipole and maintaining NHE1 structure and function., PKC-delta activates p38/MAPK, responsible for the inhibition of MMP-2 and -9 secretion, PKC-epsilon activates a pathway made of ERK1/2, mTOR and S6K responsible for the inhibition of NHE1 activity and cell migration., Data suggest that Na/H exchanger isoform one (NHE1) is critical in triple-negative breast cancer metastasis., The NHE-1 is a ubiquitously expressed cell membrane protein which regulates intracellular pH (pH(i)) and extracellular pH (pH(e)) homeostasis and cell volume., This review focuses on the role of NHE1 and OPN in cardiac remodeling and emphasizes the signaling pathways implicating OPN in the NHE1-induced hypertrophic response., CIAPIN1 over-expression decreases NHE1 expression and ERK1/2 phosphorylation., Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib., Functional studies of N266H mutation in SLC9A1 gene showed a minor effect on the level of expression and no effect on targeting of the protein, however there was a complete absence of SLC9A1 activity., the results support the anti-apoptotic role of HO-1 induced by NHE1 in the K562R cell line and IM-insensitive CML patients, the present study revealed that miR-27b is upregulated by HPV16 E7 to inhibit PPARg expression and promotes proliferation and invasion in cervical carcinoma cells., interaction of NHE1, NCX1 and CaM mediates the effects of IL6 on human hepatocellular carcinoma,
OMIM_DISEASE Lichtenstein-Knorr syndrome,
SP_COMMENT caution:The region between transmembrane regions M4 and M5 and between M6 and M7 (also termed intracellular loops IL2 and IL4, respectively) seem to be localized at least in part in the membrane. The hydrophobic region H10 is proposed to be located within the membrane., function:Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction., miscellaneous:Inhibited by amiloride and 5-amino-substituted derivatives and activated in a cooperative fashion by intracellular H(+). In quiescent cells upon growth factor stimulation, the apparent affinity for internal H(+) is increased, resulting in a persistent rise in cytoplasmic pH., PTM:O-glycosylated., PTM:Phosphorylated upon DNA damage, probably by ATM or ATR., similarity:Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family., subunit:Interacts with tescalcin, CHP and CHP2., tissue specificity:Kidney and intestine.,