Mutations in WNK1/4 (With No Lysine [K] kinases) cause autosomal dominant Gordon's syndrome (a.k.a. Pseudohypoaldosteronism Type II) characterized by hypertension, hyperkalemia, and reflecting the fact that WNK kinases are critical regulators of Na+/K+/Cl- co-transporters (CCCs) controlling cell volume and ion reabsorption in the kidney. Recently has it become clear that Wnk kinases also have important functions during development: WNK1 deficiency causes angiogenesis defects and hypoplastic atrial and ventricular heart chambers in mice and neural defects causing Hereditary Sensory and Autonomic Neuropathy type II (HSANII) in humans. At least some functions of Wnk kinases are conserved, as recent evidence suggests that Wnks have a function in neural development in mice, zebrafish, and Drosophila. We identified the single fly ortholog of Wnks as a regulator of canonical Wnt signaling, an unexpected and novel function of Wnks that appears to be similar in human cells. The canonical Wnt/?-Catenin signaling pathway is highly conserved from invertebrates to humans and has a broad and essential role in regulating proliferation of different cell types including stem cells. Interestingly, hyperactivation of Wnt signaling can lead to pulmonary arterial hypertension. Furthermore, the proliferation of certain cancer cell lines wit high ?-Catenin activity is dependent on WNK1, suggesting an intricate connection between Wnks and Wnt signaling. The role of Wnk kinases during development was previously unrecognized; therefore, how Wnk functions in this context is not understood. We will thus elucidate the functions of Wnk during development, determine the extent to which they are mediated by Wnt signaling, and identify novel Wnk effectors essential for these functions. Our research strategy will shed much needed light on how Wnk affects organogenesis and thus will likely have implications for human heart disease and cancer.
Early development is controlled by networks of tightly controlled signaling pathways. Using a molecular screen, we identified a conserved, novel, and unanticipated function for Wnk kinases in the regulation of canonical Wnt signaling. Wnk kinases, previously mainly known for the role in the regulation of ion reabsorbtion in the kidney, thus have additional roles in early development. We will determine the mechanisms how Wnk affects development and will identify novel Wnk effectors.
| Rodan, Aylin R; Jenny, Andreas (2017) WNK Kinases in Development and Disease. Curr Top Dev Biol 123:1-47 |
| Kaur, Prameet; Lam, Vanessa Yuk Man; Mannava, Anirudh Gautam et al. (2017) Membrane Targeting of Disheveled Can Bypass the Need for Arrow/LRP5. Sci Rep 7:6934 |
