Regulation of Endocytosis of ROMK Channel by WNK Kinase Family

WNK kinases are members of a novel family of serine/threonine kinases with atypical placement of the catalytic lysine. Mutations in WNK1 and WNK4 cause pseudohypoaldosteronism type 2 (PHA2), an autosomal-dominant disease characterized by hypertension and hyperkalemia. Renal outer medullary potassium channel (ROMK) is responsible for constitutive K+ secretion in the kidney. WNK1 and WNK4 stimulate the clathrin-mediated endocytosis of ROMK, which contributes to the pathogenesis of hyperkalemia in PHAII patients. Intersectin (ITSN) is a multimodular endocytic scaffold protein. The proline-rich domains of WNK1 and WNK4 bind with the Src-homology domain (SH3) of intersectin, and this interaction is important for the stimulation of endocytosis of ROMK by WNKs. Intersectin will further activate the GTPase activity of dynamin and the actin polymerization of N-WASP, and thus promote endocytosis of ROMK channel. WNK1 inhibition of ROMK is further regulated by the kinase domain conformation, which is critical for WNK1 to recruit intersectin. A shorter renal alternatively spliced form of WNK1 that lacks the kinase domain, known as kidney specific WNK1 (KSWNK1),interacts with WNK1 kinase domain and antagonizes WNK1 inhibition of ROMK. The 4a domain and the auto-inhibitory domain in KS-WNK1 are responsible for the antagonization. The antagonism of WNK1 by 4a domain of KS-WNK1 can be abolished by 2-BP (a palmitoylation inhibitor) and hydrogen peroxide (generated during K+ deficiency). These results provide a molecular mechanism for the regulation of endocytosis of ROMK by WNK kinase family.

Author dc:creator

• Wang, Hao-Ran

Contributors dc:contributor

• Huang, Chou-Long

• Protein-Serine-Threonine Kinases
• Potassium Channels, Inwardly Rectifying
• Protein Structure, Tertiary

Language dc:language

en

Identifier

760909633

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/270