IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

Dongki Yang; Chou-Long Huang; Qin Li; Insuk So; Hideaki Ando; Akihiro Mizutani; George Seki; Katsuhiko Mikoshiba; Philip J Thomas; Shmuel Muallem

doi:10.1172/JCI43475

Back

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

Journal article

Open access

Peer reviewed

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

Dongki Yang, Chou-Long Huang, Qin Li, Insuk So, Hideaki Ando, Akihiro Mizutani, George Seki, Katsuhiko Mikoshiba, Philip J Thomas and Shmuel Muallem

The Journal of clinical investigation, Vol.121(3), pp.956-965

03/2011

DOI: 10.1172/JCI43475

PMCID: PMC3049373

PMID: 21317537

Files and links (1)

url

https://doi.org/10.1172/JCI43475View

Published (Version of record) Open Access

Abstract

Fluid and HCO(3)(-) secretion are fundamental functions of epithelia and determine bodily fluid volume and ionic composition, among other things. Secretion of ductal fluid and HCO(3)(-) in secretory glands is fueled by Na(+)/HCO(3)(-) cotransport mediated by basolateral solute carrier family 4 member 4 (NBCe1-B) and by Cl(-)/HCO(3)(-) exchange mediated by luminal solute carrier family 26, member 6 (Slc26a6) and CFTR. However, the mechanisms governing ductal secretion are not known. Here, we have shown that pancreatic ductal secretion in mice is suppressed by silencing of the NBCe1-B/CFTR activator inositol-1,4,5-trisphosphate (IP(3)) receptor-binding protein released with IP(3) (IRBIT) and by inhibition of protein phosphatase 1 (PP1). In contrast, silencing the with-no-lysine (WNK) kinases and Ste20-related proline/alanine-rich kinase (SPAK) increased secretion. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities. Silencing of SPAK and IRBIT in the same ducts rescued ductal secretion due to silencing of IRBIT alone. These findings stress the pivotal role of IRBIT in epithelial fluid and HCO(3)(-) secretion and provide a molecular mechanism by which IRBIT coordinates these processes. They also have implications for WNK/SPAK kinase-regulated processes involved in systemic fluid homeostasis, hypertension, and cystic fibrosis.

Minor Histocompatibility Antigens

Humans

Gene Expression Regulation

Gene Silencing

Intracellular Signaling Peptides and Proteins

Adenosylhomocysteinase - metabolism

Cystic Fibrosis Transmembrane Conductance Regulator - metabolism

Pancreatic Ducts - metabolism

Sodium-Bicarbonate Symporters - metabolism

Lectins, C-Type - metabolism

Protein Phosphatase 1 - metabolism

Animals

WNK Lysine-Deficient Protein Kinase 1

Female

Membrane Proteins - metabolism

Mice

Parotid Gland - metabolism

Protein-Serine-Threonine Kinases - metabolism

Details

Title: Subtitle: IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway
Creators: Dongki Yang - The Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892, USA
Chou-Long Huang
Qin Li
Insuk So
Hideaki Ando
Akihiro Mizutani
George Seki
Katsuhiko Mikoshiba
Philip J Thomas
Shmuel Muallem
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.121(3), pp.956-965
DOI: 10.1172/JCI43475
PMID: 21317537
PMCID: PMC3049373
ISSN: 0021-9738
eISSN: 1558-8238
Grant note: R01 DE012309 / NIDCR NIH HHS Intramural NIH HHS R01 DK076638 / NIDDK NIH HHS DK076638 / NIDDK NIH HHS DE 12309 / NIDCR NIH HHS
Language: English
Date published: 03/2011
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984094493602771

Metrics

13 Record Views

79 Times Cited - Web of Science

See more details