Faculty Collaboration Database

Ras activates the epithelial Na(+) channel through phosphoinositide 3-OH kinase signaling. J Biol Chem 2004 Sep 03;279(36):37771-8

Date

06/25/2004

Pubmed ID

15215250

DOI

10.1074/jbc.M402176200

Scopus ID

2-s2.0-4444264303 (requires institutional sign-in at Scopus site)   77 Citations

Abstract

Aldosterone induces expression and activation of the GTP-dependent signaling switch K-Ras. This small monomeric G protein is both necessary and sufficient for activation of the epithelial Na(+) channel (ENaC). The mechanism by which K-Ras enhances ENaC activity, however, is uncertain. We demonstrate here that K-Ras activates human ENaC reconstituted in Chinese hamster ovary cells in a GTP-dependent manner. K-Ras influences ENaC activity most likely by affecting open probability. Inhibition of phosphoinositide 3-OH kinase (PI3K) abolished K-Ras actions on ENaC. In contrast, inhibition of other K-Ras effector cascades, including the MAPK and Ral/Rac/Rho cascades, did not affect K-Ras actions on ENaC. Activation of ENaC by K-Ras, moreover, was sensitive to co-expression of dominant negative p85(PI3K). The G12:C40 effector-specific double mutant of Ras, which preferentially activates PI3K, enhanced ENaC activity in a manner sensitive to inhibition of PI3K. Other effector-specific mutants preferentially activating MAPK and RalGDS signaling had no effect. Constitutively active PI3K activated ENaC independent of K-Ras with the effects of PI3K and K-Ras on ENaC not being additive. We conclude that K-Ras activates ENaC via the PI3K cascade.

Author List

Staruschenko A, Patel P, Tong Q, Medina JL, Stockand JD

MESH terms used to index this publication - Major topics in bold

Animals
CHO Cells
Cricetinae
Epithelial Sodium Channels
Guanosine Triphosphate
Microscopy, Fluorescence
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins p21(ras)
Signal Transduction
Sodium Channels