Scaffold Protein Connector Enhancer of Kinase Suppressor of Ras Isoform 3 (CNK3) Coordinates Assembly of a Multiprotein Epithelial Sodium Channel (ENaC)-regulatory Complex |
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Authors: | Rama Soundararajan Tim Ziera Eric Koo Karen Ling Jian Wang Steffen A Borden David Pearce |
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Institution: | From the ‡Division of Nephrology, Department of Medicine and ;¶Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143 and ;§Strategic Planning, Bayer Healthcare Pharmaceuticals, 13353 Berlin, Germany |
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Abstract: | Hormone regulation of ion transport in the kidney tubules is essential for fluid and electrolyte homeostasis in vertebrates. A large body of evidence has suggested that transporters and channels exist in multiprotein regulatory complexes; however, relatively little is known about the composition of these complexes or their assembly. The epithelial sodium channel (ENaC) in particular is tightly regulated by the salt-regulatory hormone aldosterone, which acts at least in part by increasing expression of the serine-threonine kinase SGK1. Here we show that aldosterone induces the formation of a 1.0–1.2-MDa plasma membrane complex, which includes ENaC, SGK1, and the ENaC inhibitor Nedd4-2, a key target of SGK1. We further show that this complex contains the PDZ domain-containing protein connector enhancer of kinase suppressor of Ras isoform 3 (CNK3). CNK3 physically interacts with ENaC, Nedd4-2, and SGK1; enhances the interactions among them; and stimulates ENaC function in a PDZ domain-dependent, aldosterone-induced manner. These results strongly suggest that CNK3 is a molecular scaffold, which coordinates the assembly of a multiprotein ENaC-regulatory complex and hence plays a central role in Na+ homeostasis. |
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Keywords: | Aldosterone Hormones Signal Transduction Sodium Channels Sodium Transport ENaC Scaffold ENaC-regulatory Complex Aldosterone Signaling |
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