High CO2 leads to Na, K-ATPase endocytosis via c-Jun amino-terminal kinase-induced LMO7b phosphorylation

Laura A. Dada*, Humberto E. Trejo Bittar, Lynn C. Welch, Olga Vagin, Nimrod Deiss-Yehiely, Aileen M. Kelly, Mairead R. Baker, Joseph Capri, Whitaker Cohn, Julian P. Whitelegge, István Vadász, Yosef Gruenbaum, Jacob I. Sznajder

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The c-Jun amino-terminal kinase (JNK) plays a role in inflammation, proliferation, apoptosis, and cell adhesion and cell migration by phosphorylating paxillin and ß-catenin. JNK phosphorylation downstream of AMP-activated protein kinase (AMPK) activation is required for high CO2 (hypercapnia)-induced Na, K-ATPase endocytosis in alveolar epithelial cells. Here, we provide evidence that during hypercapnia, JNK promotes the phosphorylation of LMO7b, a scaffolding protein, in vitro and in intact cells. LMO7b phosphorylation was blocked by exposing the cells to the JNK inhibitor SP600125 and by infecting cells with dominant-negative JNK or AMPK adenovirus. The knockdown of the endogenous LMO7b or overexpression of mutated LMO7b with alanine substitutions of five potential JNK phosphorylation sites (LMO7b-5SA) or only Ser-1295 rescued both LMO7b phosphorylation and the hypercapnia-induced Na, K-ATPase endocytosis. Moreover, high CO2 promoted the colocalization and interaction of LMO7b and the Na, K-ATPase α1 subunit at the plasma membrane, which were prevented by SP600125 or by transfecting cells with LMO7b-5SA. Collectively, our data suggest that hypercapnia leads to JNK-induced LMO7b phosphorylation at Ser-1295, which facilitates the interaction of LMO7b with Na, K-ATPase at the plasma membrane promoting the endocytosis of Na, K-ATPase in alveolar epithelial cells.

Original languageEnglish (US)
Pages (from-to)3962-3973
Number of pages12
JournalMolecular and cellular biology
Volume35
Issue number23
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Dada, L. A., Trejo Bittar, H. E., Welch, L. C., Vagin, O., Deiss-Yehiely, N., Kelly, A. M., Baker, M. R., Capri, J., Cohn, W., Whitelegge, J. P., Vadász, I., Gruenbaum, Y., & Sznajder, J. I. (2015). High CO2 leads to Na, K-ATPase endocytosis via c-Jun amino-terminal kinase-induced LMO7b phosphorylation. Molecular and cellular biology, 35(23), 3962-3973. https://doi.org/10.1128/MCB.00813-15