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1.
Int J Dev Biol ; 59(7-9): 367-77, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26679950

RESUMO

Ionic messengers signal several critical events in carcinogenesis, including metastasis, the leading cause of patient mortality. The aberrant metabolic, proliferative and anti-apoptotic nature of neoplastic cells can be traced to the abnormal expression of their ion transporters and related signalling networks. In this manuscript, we discuss Na(+)/H(+)flux, as mediated by the sodium-hydrogen exchanger isoform 1 (NHE1), a major ion transporter involved in tumourigenesis. Allosteric activation of NHE1 by external stimuli is controlled by phosphorylation of key amino acids on its cytosolic C-terminal tail, which also acts as a signal scaffold for its regulation by intracellular protein and lipid binding partners. In breast cancer cells, pH homeostasis and proton dynamics are disrupted early in transformation. This constitutively activates NHE1, causing a reversal of the plasma membrane pH gradient, resulting in a more alkaline intracellular pH and a more acidic extracellular pH. NHE1-mediated cellular alkalinization potentiates cytoskeletal remodelling, mobilizing cells for directed migration. Concomitant redistribution of NHE1 to invadopodia, where increased proton extrusion promotes proteolytic digestion of the extracellular matrix, primes cells for invasion into the bloodstream. NHE1 hyperactivity therefore heralds an important stage in cancer cell development, critically facilitating the acquisition of the invasive phenotype necessary for metastasis to occur. The potential for targeting NHE1 in the development of novel chemotherapeutic applications is explored.


Assuntos
Neoplasias da Mama/metabolismo , Carcinogênese/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Microambiente Tumoral/fisiologia , Animais , Neoplasias da Mama/patologia , Feminino , Humanos , Transporte de Íons/fisiologia , Fosforilação , Trocador 1 de Sódio-Hidrogênio
2.
Cancer Res ; 73(4): 1259-64, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23393197

RESUMO

The pH gradient in normal cells is tightly controlled by the activity of various pH-regulatory membrane proteins including the isoform protein of the Na(+)/H(+) exchanger (NHE1). NHE1 is constitutively active in a neoplastic microenvironment, dysregulating pH homeostasis and altering the survival, differentiation, and proliferation of cancer cells, thereby causing them to become tumorigenic. Cytoplasmic alkalinization in breast cancer cells occurs as a result of increased NHE1 activity and, while much is known about the pathophysiologic role of NHE1 in tumor progression with regard to ion flux, the regulation of its activity on a molecular level is only recently becoming evident. The membrane domain of NHE1 is sufficient for ion exchange. However, its activity 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. Here, we review the importance of these regulatory sites and what role they may play in the disrupted functionality of NHE1 in breast cancer metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Transdução de Sinais , Trocadores de Sódio-Hidrogênio/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7 , Modelos Biológicos , Metástase Neoplásica , Fosforilação , Trocador 1 de Sódio-Hidrogênio
3.
J Vis Exp ; (43)2010 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-20864924

RESUMO

Mammalian Toll-like receptors (TLRs) are a family of receptors that recognize pathogen-associated molecular patterns. Not only are TLRs crucial sensors of microbial (e.g., viruses, bacteria and parasite) infections, they also play an important role in the pathophysiology of infectious diseases, inflammatory diseases, and possibly in autoimmune diseases. Thus, the intensity and duration of TLR responses against infectious diseases must be tightly controlled. It follows that understanding the structural integrity of sensor receptors, their ligand interactions and signaling components is essential for subsequent immunological protection. It would also provide important opportunities for disease modification through sensor manipulation. Although the signaling pathways of TLR sensors are well characterized, the parameters controlling interactions between the sensors and their ligands still remain poorly defined. We have recently identified a novel mechanism of TLR activation by its natural ligand, which has not been previously observed. It suggests that ligand-induced TLR activation is tightly controlled by Neu1 sialidase activation. We have also reported that Neu1 tightly regulates neurotrophin receptors like TrkA and TrkB, which involve Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in complex with the receptors. The sialidase assay has been initially use to find a novel ligand, thymoquinone, in the activation of Neu4 sialidase on the cell surface of macrophages, dendritic cells and fibroblast cells via GPCR Gαi proteins and MMP-9. For TLR receptors, our data indicate that Neu1 sialidase is already in complex with TLR-2, -3 and -4 receptors, and is induced upon ligand binding to either receptor. Activated Neu1 sialidase hydrolyzes sialyl α-2,3-linked ß-galactosyl residues distant from ligand binding to remove steric hinderance to TLR-4 dimerization, MyD88/TLR4 complex recruitment, NFkB activation and pro-inflammatory cell responses. In a collaborative report, Neu1 sialidase has been shown to regulate phagocytosis in macrophage cells. Taken together, the sialidase assay has provided us with powerful insights to the molecular mechanisms of ligand-induced receptor activation. Although the precise relationship between Neu1 sialidase and the activation of TLR, Trk receptors has yet to be fully elucidated, it would represent a new or pioneering approach to cell regulation pathways.


Assuntos
Neuraminidase/metabolismo , Receptores Toll-Like/metabolismo , Animais , Células Dendríticas/enzimologia , Células Dendríticas/metabolismo , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Humanos , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Neuraminidase/análise
4.
Glycobiology ; 17(1): 10-24, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16971381

RESUMO

A direct link between receptor glycosylation and activation following natural ligand interaction has not been observed. Here, we discover a membrane sialidase-controlling mechanism that depends on ligand binding to its receptor to induce enzyme activity which targets and desialylates the receptor and, consequently, causes the induction of receptor dimerization and activation. We also identify a specific sialyl alpha-2,3-linked beta-galactosyl sugar residue of TrkA tyrosine kinase receptor, which is rapidly targeted and hydrolyzed by the sialidase. Trk-expressing cells and primary cortical neurons following stimulation with specific neurotrophic growth factors express a vigorous membrane sialidase activity. Neuraminidase inhibitors, Tamiflu, BCX1812, and BCX1827, block sialidase activity induced by nerve growth factor (NGF) in TrkA-PC12 cells and by brain-derived neurotrophic factor (BDNF) in primary cortical neurons. In contrast, the neuraminidase inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid, specific for plasma membrane ganglioside Neu3 and Neu2 sialidases has no inhibitory effect on NGF-induced pTrkA. The GM1 ganglioside specific cholera toxin subunit B applied to TrkA-PC12 cells has no inhibitory effect on NGF-induced sialidase activity. Neurite outgrowths induced by NGF-treated TrkA-PC12 and BDNF-treated PC12(nnr5) stably transfected with TrkB receptors (TrkB-nnr5) cells are significantly inhibited by Tamiflu. Our results establish a novel mode of regulation of receptor activation by its natural ligand and define a new function for cellular sialidases.


Assuntos
Fatores de Crescimento Neural/farmacologia , Neuraminidase/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Assialoglicoproteínas/química , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Embrião de Mamíferos , Ativação Enzimática/efeitos dos fármacos , Feminino , Proteínas de Membrana/metabolismo , Camundongos , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células PC12 , Gravidez , Ligação Proteica , Ratos , Receptor trkA/química
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