Intracellular pH regulation by Naâº/H⺠exchanger-1 (NHE1) is required for growth factor-induced mammary branching morphogenesis.
Dev Biol
; 365(1): 71-81, 2012 May 01.
Article
em En
| MEDLINE
| ID: mdl-22366186
ABSTRACT
Regulation of intracellular pH (pHi) and protection against cytosolic acidification is primarily a function of the ubiquitous plasma membrane Na+/H+exchanger-1 (NHE1), which uses a highly conserved process to transfer cytosolic hydrogen ions (H+) across plasma membranes in exchange for extracellular sodium ions (Na+). Growth factors, which are essential regulators of morphogenesis, have also been found to be key activators of NHE1 exchanger activity; however, the crosstalk between both has not been fully evaluated during organ development. Here we report that mammary branching morphogenesis induced by transforming growth factor-alpha (TGFα) requires PI3K-dependent NHE1-activation and subsequent pHi alkalization. Inhibiting NHE1 activity after TGFα stimulation with 10 µM of the NHE1-specific inhibitor N-Methyl-N-isobutyl Amiloride (MIA) dramatically disrupted branching morphogenesis, induced extensive proliferation, ectopic expression of the epithelial hyper-proliferative marker Keratin-6 and sustained activation of MAPK. Together these findings indicate a novel developmental signaling cascade involving TGFα>PI3K>NHE1>pHi alkalization, which leads to a permissible environment for MAPK negative feedback inhibition and thus regulated mammary branching morphogenesis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Trocadores de Sódio-Hidrogênio
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Proteínas de Transporte de Cátions
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Glândulas Mamárias Animais
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article