Intersectin links WNK kinases to endocytosis of ROMK1
| Autor: | Chou Long Huang, Haoran Wang, Guocheng He, Shao Kuei Huang |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Scaffold protein
Proline Endocytic cycle Protein Serine-Threonine Kinases Biology Kidney Endocytosis Cell Line Minor Histocompatibility Antigens src Homology Domains WNK Lysine-Deficient Protein Kinase 1 Humans Potassium Channels Inwardly Rectifying Kinase activity urogenital system Kinase Intracellular Signaling Peptides and Proteins General Medicine WNK1 Clathrin WNK4 Cell biology Adaptor Proteins Vesicular Transport Gene Expression Regulation Biochemistry Research Article |
| Zdroj: | Journal of Clinical Investigation. 117:1078-1087 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci30087 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|