ArticleThe Journal of biological chemistry2014
AKT and GSK-3 are necessary for direct ezrin binding to NHE3 as part of a C-terminal stimulatory complex: role of a novel Ser-rich NHE3 C-terminal motif in NHE3 activity and trafficking.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 20 citations in OpenAlex.
- A biophysical perspective of the regulatory mechanisms of ezrin/radixin/moesin proteins.Biophysical reviews · 2022Review
- Identification of Intestinal NaCl Absorptive-Anion Secretory Cells: Potential Functional Significance.Frontiers in physiology · 2022Review
- The recycling regulation of sodium-hydrogen exchanger isoform 3(NHE3) in epithelial cells.Cell cycle (Georgetown, Tex.) · 2021Review
- cAMP Stimulates SLC26A3 Activity in Human Colon by a CFTR-Dependent Mechanism That Does Not Require CFTR Activity.Cellular and molecular gastroenterology and hepatology · 2019Article
- Both NHERF3 and NHERF2 are necessary for multiple aspects of acute regulation of NHE3 by elevated CaAmerican journal of physiology. Gastrointestinal and liver physiology · 2018Article
- Phosphorylation of NHE3-SMolecular biology of the cell · 2017Article
- The clinical significance of changes in ezrin expression in osteosarcoma of children and young adults.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging.Theranostics · 2016Review
- The NHERF2 sequence adjacent and upstream of the ERM-binding domain affects NHERF2-ezrin binding and dexamethasone stimulated NHE3 activity.The Biochemical journal · 2015Article
- Sorting nexin 27 regulates basal and stimulated brush border trafficking of NHE3.Molecular biology of the cell · 2015Article
- Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity.American journal of physiology. Cell physiology · 2015Article
- The Na+/H+ Exchanger-3 (NHE3) Activity Requires Ezrin Binding to Phosphoinositide and Its Phosphorylation.PloS one · 2015Article
- Molecular mechanisms and regulation of urinary acidification.Comprehensive Physiology · 2014Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Basal activity of the BB Na(+)/H(+) exchanger NHE3 requires multiprotein complexes that form on its C terminus. One complex stimulates basal NHE3 activity and contains ezrin and phosphoinositides as major components; how it stimulates NHE3 activity is not known. This study tested the hypothesis that ezrin dynamically associates with this complex, which sets ezrin binding. NHE3 activity was reduced by an Akti. This effect was eliminated if ezrin binding to NHE3 was inhibited by a point mutant. Recombinant AKT phosphorylated NHE3 C terminus in the domain ezrin directly binds. This domain (amino acids 475-589) is predicted to be α-helical and contains a conserved cluster of three serines (Ser(515), Ser(522), and Ser(526)). Point mutations of two of these (S515A, S515D, or S526A) reduced basal NHE3 activity and surface expression and had no Akti inhibition. S526D had NHE3 activity equal to wild type with normal Akti inhibition. Ezrin binding to NHE3 was regulated by Akt, being eliminated by Akti. NHE3-S515A and -S526D did not bind ezrin; NHE3-S515D had reduced ezrin binding; NHE3-S526D bound ezrin normally. NHE3-Ser(526) is predicted to be a GSK-3 kinase phosphorylation site. A GSK-3 inhibitor reduced basal NHE3 activity as well as ezrin-NHE3 binding, and this effect was eliminated in NHE3-S526A and -S526D mutants. The conclusions were: 1) NHE3 basal activity is regulated by a signaling complex that is controlled by sequential effects of two kinases, Akt and GSK-3, which act on a Ser cluster in the same NHE3 C-terminal domain that binds ezrin; and 2) these kinases regulate the dynamic association of ezrin with NHE3 to affect basal NHE3 activity.
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