TAILIEUCHUNG - Báo cáo khoa học: Distinct pathways for the involvement of WNK4 in the signaling of hypertonicity and EGF

WNK4 kinase mutations produce the autosomal dominant disorder famil-ial hyperkalemia and hypertension (FHH), also known as pseudohypo-aldosteronism type II, by a molecular mechanism that is not completely understood. | ỊFEBS Journal Distinct pathways for the involvement of WNK4 in the signaling of hypertonicity and EGF Miriam Shaharabany1 2 Eliezer J. Holtzman2 3 Haim Mayan3 4 Koret Hirschberg3 5 Rony Seger6 and Zvi Farfel1 3 4 1 Laboratory of BiochemicalPharmacology Sheba MedicalCenter TelHashomer Israel 2 Nephrology Institute Sheba MedicalCenter TelHashomer Israel 3 Sackler Schoolof Medicine TelAviv University Israel 4 Department of Medicine E Sheba MedicalCenter TelHashomer Israel 5 Department of Pathology TelAviv University Israel 6 Department of BiologicalRegulation Weitzman Institute of Science Rehovot Israel Keywords cell traffic EGF hypertonicity signal transduction WNK kinase Correspondence Z. Farfel Department of Medicine E Sheba MedicalCenter TelHashomer 52621 Israel Fax 97 235 302460 Tel 97 235 302437 E-mail farfel@ Received 21 August 2007 revised 16 January 2008 accepted 4 February 2008 doi WNK4 kinase mutations produce the autosomal dominant disorder familial hyperkalemia and hypertension FHH also known as pseudohypoaldosteronism type II by a molecular mechanism that is not completely understood. In vitro experiments in frog oocytes showed that WNK4 affects ion transport systems such as the Na-Cl cotransporter and the renal outer medullary potassium channel. Some features of FHH suggest that long-term effects are involved in WNK4 signaling. In addition WNK1 and WNK2 paralogs of WNK4 were shown to be involved in MAP kinase signaling. We therefore investigated possible WNK4 involvement in MAP kinase signaling. We stimulated HEK 293 cells overexpressing WNK4 by hypertonicity or using EGF and measured phosphorylation of extracellular signal-regulated kinase ERK 1 2 and p38. WNK4 augmented the phosphorylation of ERK1 2 and p38 in response to both hypertonicity and EGF. The FHH-producing and kinase-deficient mutants behaved similarly to wild-type WNK4. Hypertonicity stimulation was accompanied by cellular relocalization of .

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