{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWNK3 is a serine/threonine kinase that plays a central role in regulating electrolyte homeostasis by modulating the activity and surface expression of multiple ion transporters. In renal epithelia, WNK3 interacts with other WNK family members—such as WNK1 and WNK4—to positively regulate the thiazide‐sensitive Na⁺–Cl⁻ cotransporter (NCC), thereby influencing sodium reabsorption and blood pressure control. In this context, the kinase‐dependent actions of WNK3 not only counterbalance the inhibitory effects of WNK4 but also engage signaling pathways that include SGK1 activation, as well as the regulation of TRPV5/TRPV6 Ca²⁺ channels to enhance Ca²⁺ uptake. Moreover, various splice isoforms of WNK3 have been shown to exhibit tissue‐specific functions, underlining its importance in fine‐tuning ion transport in both kidney and brain."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in ion transport, WNK3 critically influences cell volume regulation and survival. Its kinase activity modulates the balance between the chloride-coupled cotransporters—activating the Na⁺–K⁺–Cl⁻ cotransporter and inhibiting the K⁺–Cl⁻ cotransporters—to coordinate regulatory volume decrease (RVD) and regulatory volume increase (RVI) in response to osmotic challenges. Extracellular ions, such as potassium, can directly inhibit WNK3 autophosphorylation and downstream signaling, highlighting a chloride-independent regulatory mechanism. Furthermore, WNK3 has been implicated in protective cellular responses where its activity delays the onset of apoptosis by interacting with procaspase-3 and heat-shock protein 70, while its functional inhibition (or suppression by interacting proteins like LINGO-1) potentiates cell death. These observations are particularly relevant in the context of ischemic injury and glioma invasion, where proper cell volume regulation is essential."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical roles in renal physiology, WNK3 is widely expressed in the brain where it contributes to diverse neurological functions. Aberrant WNK3 signaling—whether through alternative splicing, altered expression, or microdeletions affecting its coding sequence—has been associated with neurodevelopmental disorders such as autism, schizophrenia, and epilepsy, as well as with pathologies including cerebral ischemia and glioma. In neurons, WNK3 helps regulate chloride homeostasis, thereby influencing γ-aminobutyric acid (GABA) neurotransmission, while its dysregulation has been linked to granule cell dispersion in temporal lobe epilepsy. Recent studies further implicate WNK3 in cancer biology through its positive regulation of PD-L1 expression, which modulates antitumor immune responses and may represent a novel target for cancer immunotherapy. Together, these multifaceted roles underscore the therapeutic potential of targeting WNK3 in both neurological disorders and cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chao-Ling Yang, Xiaoman Zhu, David H Ellison "}, {"type": "b", "children": [{"type": "t", "text": "The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI32033"}], "href": "https://doi.org/10.1172/JCI32033"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17975670"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17975670"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Charles J Heise, Bing-e Xu, Staci L Deaton, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.103432"}], "href": "https://doi.org/10.1074/jbc.M110.103432"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20525693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20525693"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mark Glover, Annie Mercier Zuber, Kevin M O'Shaughnessy "}, {"type": "b", "children": [{"type": "t", "text": "Renal and brain isoforms of WNK3 have opposite effects on NCCT expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Soc Nephrol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1681/ASN.2008050542"}], "href": "https://doi.org/10.1681/ASN.2008050542"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19470686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19470686"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Pedro San-Cristobal, José Ponce-Coria, Norma Vázquez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Renal Physiol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajprenal.90396.2008"}], "href": "https://doi.org/10.1152/ajprenal.90396.2008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18701621"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18701621"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wei Zhang, Tao Na, Ji-Bin Peng "}, {"type": "b", "children": [{"type": "t", "text": "WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Renal Physiol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajprenal.90229.2008"}], "href": "https://doi.org/10.1152/ajprenal.90229.2008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18768590"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18768590"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Silvia Cruz-Rangel, Zesergio Melo, Norma Vázquez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Similar effects of all WNK3 variants on SLC12 cotransporters."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00070.2011"}], "href": "https://doi.org/10.1152/ajpcell.00070.2011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21613606"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21613606"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Dagmara Lagnaz, Juan Pablo Arroyo, María Chávez-Canales, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WNK3 abrogates the NEDD4-2-mediated inhibition of the renal Na+-Cl- cotransporter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Renal Physiol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajprenal.00574.2013"}], "href": "https://doi.org/10.1152/ajprenal.00574.2013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24920754"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24920754"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Dexuan Wang, Yiqian Zhang, Jinhua Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WNK3 Kinase Enhances the Sodium Chloride Cotransporter Expression via an ERK 1/2 Signaling Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nephron (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000447717"}], "href": "https://doi.org/10.1159/000447717"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27467688"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27467688"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Gulnaz Begum, Hui Yuan, Kristopher T Kahle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of WNK3 Kinase Signaling Reduces Brain Damage and Accelerates Neurological Recovery After Stroke."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stroke (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/STROKEAHA.115.008939"}], "href": "https://doi.org/10.1161/STROKEAHA.115.008939"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26069258"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26069258"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "F Veríssimo, E Silva, J D Morris, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1209449"}], "href": "https://doi.org/10.1038/sj.onc.1209449"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16501604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16501604"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Silvia Cruz-Rangel, Gerardo Gamba, Gerardo Ramos-Mandujano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Influence of WNK3 on intracellular chloride concentration and volume regulation in HEK293 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pflugers Arch (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00424-012-1137-4"}], "href": "https://doi.org/10.1007/s00424-012-1137-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22864523"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22864523"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Zhaohuan Zhang, Xiaohui Xu, Zhenghua Xiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.447771"}], "href": "https://doi.org/10.1074/jbc.M112.447771"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23482566"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23482566"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "John M Pleinis, Logan Norrell, Radha Akella, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WNKs are potassium-sensitive kinases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00456.2020"}], "href": "https://doi.org/10.1152/ajpcell.00456.2020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33439774"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33439774"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Dominique Arion, David A Lewis "}, {"type": "b", "children": [{"type": "t", "text": "Altered expression of regulators of the cortical chloride transporters NKCC1 and KCC2 in schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Gen Psychiatry (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/archgenpsychiatry.2010.114"}], "href": "https://doi.org/10.1001/archgenpsychiatry.2010.114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20819979"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20819979"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Y Qiao, X Liu, C Harvard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autism-associated familial microdeletion of Xp11.22."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1399-0004.2008.01028.x"}], "href": "https://doi.org/10.1111/j.1399-0004.2008.01028.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18498374"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18498374"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Brian R Haas, Vishnu A Cuddapah, Stacey Watkins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "With-No-Lysine Kinase 3 (WNK3) stimulates glioma invasion by regulating cell volume."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00203.2011"}], "href": "https://doi.org/10.1152/ajpcell.00203.2011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21813709"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21813709"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Simon Holden, James Cox, F Lucy Raymond "}, {"type": "b", "children": [{"type": "t", "text": "Cloning, genomic organization, alternative splicing and expression analysis of the human gene WNK3 (PRKWNK3)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2004.03.009"}], "href": "https://doi.org/10.1016/j.gene.2004.03.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15194194"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15194194"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Kyoung Hoon Jeong, Se Hoon Kim, Yun Ho Choi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased expression of WNK3 in dispersed granule cells in hippocampal sclerosis of mesial temporal lobe epilepsy patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Epilepsy Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.eplepsyres.2018.09.006"}], "href": "https://doi.org/10.1016/j.eplepsyres.2018.09.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30253317"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30253317"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Hyun Ju Yoon, Gi-Cheon Kim, Sejin Oh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Mol Med (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s12276-022-00876-z"}], "href": "https://doi.org/10.1038/s12276-022-00876-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36357569"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36357569"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Ya-Ting Gong, Mu-Yao Wu, Jia-Feng Tang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Advances in the study of the role and molecular mechanism of with‑no‑lysine kinase 3 in nervous system diseases (Review)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2021.12032"}], "href": "https://doi.org/10.3892/mmr.2021.12032"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33760209"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33760209"}]}]}]}