Structural Dynamics and Regulation of the Mammalian SLC9A Family of Na+/H+ Exchangers

Hendus-Altenburger, Ruth; Kragelund, Birthe B.; Pedersen, Stine Falsig

doi:10.1016/b978-0-12-800223-0.00002-5

Cited by 74 publications

(108 citation statements)

References 259 publications

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“…NHE1 can also be activated by the binding of intracellular signal proteins and lipids to the Cterminal regulatory domain (43,48,51). While the transmembrane domain of NHEs are highly conserved across the different isoforms, the cytosolic domain exhibits considerable variability.…”

Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

“…Many of NHE1's interactions with its lipid and protein binding partners tend to be on the C-terminal domain proximal to the membrane, while the distal end of the tail, spanned by amino acids 636 to 815, is where the majority of phosphorylation sites are located (48).…”

Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

“…This is followed by a hydrophilic COOH-terminal cytosolic domain (amino acids 501-815). The cytosolic domain regulates ion flux and its actions are modified by phosphorylation and the binding of intracellular proteins and lipids (44,48).…”

Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

“…Several different serine/threonine kinases can activate NHE1 by phosphorylation, in addition to the exchanger's activation by its intracellular binding partners (extensively reviewed in (48,51,53). Examples of kinase-mediated activators of NHE1 include: extracellular signal regulated kinases ERK1/2 which are important in the activation of NHE1 in response to intracellular acidosis, and for which NHE1 serves as a signal scaffold (54,55); AKT (protein kinase B) which activates NHE1 in response to insulin and platelet-derived growth factor in fibroblasts (56), but inhibits NHE1 activity in cardiomyocytes (57); -Raf which phosphorylates NHE1 at amino acid threonine 653 (58); and p90 ribosomal S6 kinase (p90 RSK ) which phosphorylates NHE1 at serine 703, activating the exchanger in response to serum (59).…”

Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

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Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

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Please cite this article as: Amith Schammim Ray, Fliegel Larry.Na+/H+ exchangermediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics.Seminars in Cancer Biology http://dx.doi. org/10.1016/j.semcancer.2017.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abstract (250 words):Breast cancer is the leading cause of cancer-related death in women in Europe and North America, and metastasis is the primary cause of fatality in patients with breast cancer. While some breast cancers are quite treatable, the triple-negative breast cancers are more metastatic and resistant to chemotherapy. There is clearly an urgent need for better treatments for this form of the disease. Breast cancer is characterized by genetically complex intra-tumour heterogeneity, particularly within the triple-negative clinical subtype. This complicates treatment options, so the development of specifically targeted chemotherapy for less treatable forms is critical.Dysregulation of pH homeostasis is a common factor in breast tumour cells. This occurs in concert with a metabolic switch to aerobic glycolysis that occurs at the onset of oncogenic transformation. The Na + /H + exchanger isoform 1 (NHE1) is the major pH regulatory protein involved in the increased proton extrusion of breast cancer cells. Its increased activity results in intracellular alkalinisation and extracellular acidification that drives cancer progression. The acidification of the extracellular tumour microenvironment also contributes to the development of chemotherapy resistance. In this review, we outline the role of H + as a carcinogenic signal and the role and regulation of NHE1 as a trigger for metastasis. We review recent evidence supporting the use of pharmacological inhibitors of NHE1 as a viable treatment option for triplenegative breast cancer.

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Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

See 2 more Smart Citations

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

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“…The remaining 315 amino acids form a long C-terminal tail, located in the cytoplasm, that acts as a regulatory domain. 32 While a portion of the protein required for transport of cations across the membrane has been localized to a handful of amino acid residues within the membrane domain, 34 the exact mechanism by which cation transport occurs is still under investigation. In one model, TMs 4 and 11 form a central core, while TM2 creates two funnels that shape the path for transmembrane cation transport and residues in TM5 serve as the cation-binding site.…”

Section: The Structure Of Nhe1mentioning

confidence: 99%

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension

Huetsch

Shimoda

2015

Pulm. circ.

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Intracellular pH (pH i ) homeostasis is key to the functioning of vascular smooth muscle cells, including pulmonary artery smooth muscle cells (PASMCs). Sodium-hydrogen exchange (NHE) is an important contributor to pH i control in PASMCs. In this review, we examine the role of NHE in PASMC function, in both physiologic and pathologic conditions. In particular, we focus on the contribution of NHE to the PASMC response to hypoxia, considering both acute hypoxic pulmonary vasoconstriction and the development of pulmonary vascular remodeling and pulmonary hypertension in response to chronic hypoxia. Hypoxic pulmonary hypertension remains a disease with limited therapeutic options. Thus, this review explores past efforts at disrupting NHE signaling and discusses the therapeutic potential that such efforts may have in the field of pulmonary hypertension.

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Regulation of organelle function by metformin

Kim

You

2017

IUBMB Life

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Metformin ameliorates hyperglycemia without the side effects of lactic acidosis or hypoglycemia. Metformin lowers the blood glucose level by decreasing hepatic glucose production in the liver and by increasing glucose uptake in the muscle. Recent studies show that metformin induces cell death in certain cancer cell lines by interfering with the metabolism of the cancer cells. Therefore, understanding the mechanisms of action for metformin will provide insights into how to better treat diabetes and other metabolic disorders and also into the development of new therapeutic drugs. One of the best understood molecular targets of metformin is the mitochondrial complex I. However, given metformin's broad effects on metabolism, it could act on multiple targets. In this review, we summarize current findings in metformin's mechanisms of action regarding its known targets in mitochondria and known effects in cancer cell lines. Then, we introduce endosomal Na /H exchangers and the V-ATPase as new potential targets of metformin's action. Finally, we will discuss the hypothesis that metformin directly acts on endosome/lysosome regulation so as to regulate metabolism and ultimately alleviate type 2 diabetes. © 2017 IUBMB Life, 69(7):459-469, 2017.

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Structural Dynamics and Regulation of the Mammalian SLC9A Family of Na+/H+ Exchangers

Cited by 74 publications

References 259 publications

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension

Regulation of organelle function by metformin

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Structural Dynamics and Regulation of the Mammalian SLC9A Family of Na+/H+ Exchangers

Cited by 74 publications

References 259 publications

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Na+/H+ Exchange and Hypoxic Pulmonary Hypertension

Regulation of organelle function by metformin

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Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension