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Cell Signal. 2008 Oct;20(10):1762-8. doi: 10.1016/j.cellsig.2008.06.002. Epub 2008 Jun 14.

WNK2 modulates MEK1 activity through the Rho GTPase pathway.

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Centre of Human Genetics, National Health Institute, Lisbon, Portugal.


WNK protein kinases form a kinase subfamily expressed in multi-cellular organisms and the human genome encodes four distinct WNK genes. Human WNK2 has been recently identified as a cell growth regulator that modulates activation of the ERK1/2 protein kinase and is epigenetically silenced in gliomas. Here we provide mechanistic insight into how WNK2 affects ERK activation. We found that WNK2 depletion decreased RhoA activation and promoted GTP-loading of Rac1, leading to stimulation of the Rac1-effector PAK1, which is the kinase responsible for subsequent phosphorylation of MEK1 at serine 298, thereby increasing MEK affinity towards ERK1/2. We propose that WNK2 controls a RhoA-mediated cross-talk mechanism that regulates the efficiency with which MEK1 can activate ERK1/2 upon growth factor stimulation.

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