Fig. 1

Overview of the WNK pathway and its connection to major cancer-associated signaling pathways discussed in the review. Activated WNK kinases phosphorylate and activate downstream substrate kinases OSR1 and SPAK, forming the core module of the WNK pathway (indicated by black dashed-line box). WNK signaling regulates several ion channels and cation-chloride-cotransporters via OSR1/SPAK-dependent and independent interactions. WNKs act both upstream and downstream of the PI3K-AKT pathway, which may affect AKT-mediated regulation of angiogenesis. WNKs exert direct inhibitory effects on the TGF-β signaling pathway, but OSR1 and SPAK can activate TGF-β signaling through Smad2/3. These opposing effects are likely at the root of context-dependent signaling between WNKS and TGF-β. SPAK is a known regulator of the NF-κB pathway, which may in turn be subject to upstream WNK signaling