Intracellular pH regulation by Na⁺/H⁺ exchanger-1 (NHE1) is required for growth factor-induced mammary branching morphogenesis

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• 作者：Edmund C. Jenkins Jr.^a ; ^b ; Shawon Debnath^a ; ^d ; Stephen Gundry^c ; Sajini Gundry^a ; Umit Uyar^c ; Jimmie E. Fata^a ; ^b ; ^d ; ^{jimmie.fata@csi.cuny.edu}
• 关键词：Mammary development ; Branching morphogenesis ; Sodium hydrogen exchanger ; NHE1 ; Intracellular pH ; Transforming growth factor-alpha
• 刊名：Developmental Biology
• 出版年：2012
• 期刊代码：167_00121606
• 类别：bio
• 出版时间：1 May, 2012
• 卷：365
• 期：1
• 页码：71-81
• 文件大小：1389 K

摘要

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 (TGF伪) requires PI3K-dependent NHE1-activation and subsequent pHi alkalization. Inhibiting NHE1 activity after TGF伪 stimulation with 10 渭M 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 TGF伪 > PI3K > NHE1 > pHi alkalization, which leads to a permissible environment for MAPK negative feedback inhibition and thus regulated mammary branching morphogenesis.