Journal article
Intersectin links WNK kinases to endocytosis of ROMK1
The Journal of clinical investigation, Vol.117(4), pp.1078-1087
04/02/2007
DOI: 10.1172/JCI30087
PMCID: PMC1821066
PMID: 17380208
Abstract
With-no-lysine (WNK) kinases are a novel family of protein kinases characterized by an atypical placement of the catalytic lysine. Mutations of 2 family members,
WNK1
and
WNK4
, cause pseudohypoaldosteronism type 2 (PHA2), an autosomal-dominant disease characterized by hypertension and hyperkalemia. WNK1 and WNK4 stimulate clathrin-dependent endocytosis of renal outer medullar potassium 1 (ROMK1), and PHA2-causing mutations of WNK4 increase the endocytosis. How WNKs stimulate endocytosis of ROMK1 and how mutations of WNK4 increase the endocytosis are unknown. Intersectin (ITSN) is a multimodular endocytic scaffold protein. Here we show that WNK1 and WNK4 interacted with ITSN and that the interactions were crucial for stimulation of endocytosis of ROMK1 by WNKs. The stimulation of endocytosis of ROMK1 by WNK1 and WNK4 required specific proline-rich motifs of WNKs, but did not require their kinase activity. WNK4 interacted with ROMK1 as well as with ITSN. Disease-causing WNK4 mutations enhanced interactions of WNK4 with ITSN and ROMK1, leading to increased endocytosis of ROMK1. These results provide a molecular mechanism for stimulation of endocytosis of ROMK1 by WNK kinases.
Details
- Title: Subtitle
- Intersectin links WNK kinases to endocytosis of ROMK1
- Creators
- Guocheng He - Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAHao-Ran Wang - Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAShao-Kuei Huang - Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAChou-Long Huang - Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.117(4), pp.1078-1087
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI30087
- PMID
- 17380208
- PMCID
- PMC1821066
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 04/02/2007
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094219202771
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