Na+/H+ Exchangers of Mammalian Cells

Orlowski, John; Grinstein, Sergio

doi:10.1074/jbc.272.36.22373

Cited by 551 publications

(451 citation statements)

References 66 publications

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“…These observations implicate pH regulating transporters that are active at low extracellular pH. These include the sodium proton exchanger (NHE) [Orlowski and Grinstein, 1997], the H þ -linked monocarboxylate exchanger (MCT) [Halestrap and Price, 1999]. Recent research indicates that the plasma membrane ATP synthase may be localized in a plasma membrane microdomain where it generates ATP on the cell surface thus it may not directly affect intracellular pH [Moser et al, 2003].…”

Section: Other Factors Affecting Regulation Ofmentioning

confidence: 99%

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

Wahl

Kenan

Gonzalez-Gronow

et al. 2005

J of Cellular Biochemistry

114

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Tumor growth requires the development of new vessels that sprout from pre-existing normal vessels in a process known as ''angiogenesis'' [Folkman (1971) N Engl J Med 285:1182-1186. These new vessels arise from local capillaries, arteries, and veins in response to the release of soluble growth factors from the tumor mass, enabling these tumors to grow beyond the diffusion-limited size of approximately 2 mm diameter. Angiostatin, a naturally occurring inhibitor of angiogenesis, was discovered based on its ability to block tumor growth in vivo by inhibiting the formation of new tumor blood vessels [O'Reilly et al. (1994a) Cold Spring Harb Symp Quant Biol 59:471-482]. Angiostatin is a proteolytically derived internal fragment of plasminogen and may contain various members of the five plasminogen ''kringle'' domains, depending on the exact sites of proteolysis. Different forms of angiostatin have measurably different activities, suggesting that much remains to be elucidated about angiostatin biology. A number of groups have sought to identify the native cell surface binding site(s) for angiostatin, resulting in at least five different binding sites proposed for angiostatin on the surface of endothelial cells (EC). This review will consider the data supporting all of the various reported angiostatin binding sites and will focus particular attention on the angiostatin binding protein identified by our group: F 1 F O ATP synthase. There have been several developments in the quest to elucidate the mechanism of action of angiostatin and the regulation of its receptor. The purpose of this review is to describe the highlights of research on the mechanism of action of angiostatin, its' interaction with ATP synthase on the EC surface, modulators of its activity, and issues that should be explored in future research related to angiostatin and other anti-angiogenic agents.

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Section: Other Factors Affecting Regulation Ofmentioning

confidence: 99%

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

Wahl

Kenan

Gonzalez-Gronow

et al. 2005

J of Cellular Biochemistry

114

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“…[3][4][5] NHE1, the housekeeping isoform of the Na þ /H þ exchanger, is ubiquitously distributed in most tissues and has an important role in the regulation of pH i by exchanging intracellular protons [H þ ] i for extracellular sodium [Na þ ] e . [6][7][8] The transformed cells and tumor cells differ from normal tissues in that they have constitutive NHE1 activity at resting pH i , resulting in an increased pH i . 1,9 Intracellular alkalinization induced by the activation of NHE1 in tumor cells has been shown to play key role in the maintenance and progression of the neoplastic state.…”

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confidence: 99%

The role of translation elongation factor eEF1A in intracellular alkalinization-induced tumor cell growth

Kim

Namkung

Yoon

et al. 2009

Laboratory Investigation

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The formation of a pH gradient, which is characterized by intracellular alkalinization and extracellular acidification, plays a key role in the growth and metastasis of tumor cells. However, the underlying mechanisms of alkalinization-induced cell growth are not known. In this study, we investigated the roles of eukaryotic translation elongation factor 1 a (eEF1A) in alkalinization-induced cell growth. In all cell lines tested (NIH3T3, HEK293, and HeLa), cell growth was affected by the modulation of intracellular pH. In general, weak intracellular alkalinization produced increased cell growth, whereas intracellular acidification resulted in decreased cell growth. It is interesting to note that portions of actin-bound eEF1A proteins were gradually reduced from acidic to alkaline conditions, suggesting an increase in levels of functionally active, free-form eEF1A. Over-expression of eEF1A caused increased cell growth in HeLa cells. It should be noted that dissociation of eEF1A from actin by transfection with the actin-binding domain deleted eEF1A construct further increased cell growth under acidic conditions, whereas most of the intact eEF1A was bound to actin. Conversely, knockdown of eEF1A by treatment with eEF1A1 and eEF1A2 siRNAs nullified the effects of alkalinization-induced cell growth. The above findings suggest that an increase in free-form eEF1A under alkaline conditions plays a critical role in alkalinization-induced cell growth.

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“…The mammalian Na ϩ /H ϩ exchanger isoform 1 (NHE1) 1 is a ubiquitously expressed integral membrane protein that mediates the removal of one intracellular proton in exchange for one extracellular sodium ion (1). NHE1 thereby protects cells from intracellular acidification (2,3); and stimulation of its activity promotes cell growth and differentiation (2) and regulates sodium fluxes and cell volume after osmotic shrinkage (2, 3).…”

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confidence: 99%

“…NHE1 is composed of two domains as follows: an N-terminal membrane domain of ϳ500 amino acids and a C-terminal regulatory domain of about 315 amino acids (1,4) (Fig. 1).…”

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confidence: 99%

Structural and Functional Characterization of Transmembrane Segment IV of the NHE1 Isoform of the Na+/H+ Exchanger

Slepkov¹,

Rainey

Li³

et al. 2005

Journal of Biological Chemistry

150

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The Na ؉ /H ؉ exchanger isoform 1 is a ubiquitously expressed integral membrane protein that regulates intracellular pH in mammals. We characterized the structural and functional aspects of the critical transmembrane (TM) segment IV. Each residue was mutated to cysteine in cysteineless NHE1. TM IV was exquisitely sensitive to mutation with 10 of 23 mutations causing greatly reduced expression and/or activity. The Phe 161 3 Cys mutant was inhibited by treatment with the water-soluble sulfhydryl-reactive compounds [2-(trimethylammonium)ethyl]methanethiosulfonate and [2-sulfonatoethyl]methanethiosulfonate, suggesting it is a pore-lining residue. The structure of purified TM IV peptide was determined using high resolution NMR in a CD 3 OH:CDCl 3 :H 2 O mixture and in Me 2 SO. In CD 3 OH: CDCl 3 :H 2 O, TM IV was structured but not as a canonical ␣-helix. Residues Asp 159 -Leu 162 were a series of ␤-turns; residues Leu 165 -Pro 168 showed an extended structure, and residues Ile 169 -Phe 176 were helical in character. These three structured regions rotated quite freely with respect to the others. In Me 2 SO, the structure was much less defined. Our results demonstrate that TM IV is an unusually structured transmembrane segment that is exquisitely sensitive to mutagenesis and that Phe 161 is a pore-lining residue.

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Na+/H+ Exchangers of Mammalian Cells

Cited by 551 publications

References 66 publications

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

The role of translation elongation factor eEF1A in intracellular alkalinization-induced tumor cell growth

Structural and Functional Characterization of Transmembrane Segment IV of the NHE1 Isoform of the Na+/H+ Exchanger

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