WNK1 Activates ERK5 by an MEKK2/3-dependent Mechanism

WNK1 belongs to a unique protein kinase family that lacks the catalytic lysine in its normal position. Mutations in human WNK1 and WNK4 have been implicated in causing a familial form of hypertension. Here we report that overexpression of WNK1 led to increased activity of cotransfected ERK5 in HEK29...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-02, Vol.279 (9), p.7826-7831
Main Authors: Xu, Bing-e, Stippec, Steve, Lenertz, Lisa, Lee, Byung-Hoon, Zhang, Wei, Lee, Youn-Kyoung, Cobb, Melanie H.
Format: Article
Language:English
Subjects:
Butadienes - pharmacology
Cell Line
Enzyme Activation - drug effects
Enzyme Inhibitors - pharmacology
Epidermal Growth Factor - pharmacology
ERK5 protein
Gene Expression
HeLa Cells
Humans
Immunosorbent Techniques
Intracellular Signaling Peptides and Proteins
MAP Kinase Kinase 5
MAP Kinase Kinase Kinase 2
MAP Kinase Kinase Kinase 3
MAP Kinase Kinase Kinases - analysis
MAP Kinase Kinase Kinases - physiology
MEK5 protein
MEKK2 protein
MEKK3 protein
Minor Histocompatibility Antigens
Mitogen-Activated Protein Kinase 7
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - genetics
Mitogen-Activated Protein Kinases - metabolism
Mutagenesis, Site-Directed
Nitriles - pharmacology
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - physiology
Recombinant Proteins
RNA, Small Interfering - pharmacology
Transfection
WNK Lysine-Deficient Protein Kinase 1
WNK1 protein
WNK4 protein
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Summary:WNK1 belongs to a unique protein kinase family that lacks the catalytic lysine in its normal position. Mutations in human WNK1 and WNK4 have been implicated in causing a familial form of hypertension. Here we report that overexpression of WNK1 led to increased activity of cotransfected ERK5 in HEK293 cells. ERK5 activation was blocked by the MEK5 inhibitor U0126 and expression of a dominant negative MEK5 mutant. Expression of dominant negative mutants of MEKK2 and MEKK3 also blocked activation of ERK5 by WNK1. Moreover, both MEKK2 and MEKK3 coimmunoprecipitated with endogenous WNK1 from cell lysates. WNK1 phosphorylated both MEKK2 and -3 in vitro, and MEKK3 was activated by WNK1 in 293 cells. Finally, ERK5 activation by epidermal growth factor was attenuated by suppression of WNK1 expression using small interfering RNA. Taken together, these results place WNK1 in the ERK5 MAP kinase pathway upstream of MEKK2/3.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M313465200