WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth Journal Article

   

Authors:	Duan, S.; Agger, K.; Messling, J. E.; Nishimura, K.; Han, X.; Peña-Rømer, I.; Shliaha, P.; Damhofer, H.; Douglas, M.; Kohli, M.; Pal, A.; Asad, Y.; Van Dyke, A.; Reilly, R.; Köchl, R.; Tybulewicz, V. L. J.; Hendrickson, R. C.; Raynaud, F. I.; Gallipoli, P.; Poulogiannis, G.; Helin, K.
Article Title:	WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth
Abstract:	The lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression. © The Author(s) 2025.
Keywords:	signal transduction; controlled study; protein phosphorylation; human cell; genetics; leukemia, myeloid, acute; cancer growth; nonhuman; cell proliferation; mouse; animal; metabolism; animals; mice; animal tissue; apoptosis; gene expression; animal experiment; animal model; in vivo study; in vitro study; pathology; cell line, tumor; protein serine threonine kinase; phosphorylation; leukemia cell; tumor cell line; molecular analysis; amino acid; amino acids; amino acid transport; inhibition; cell; mammalian target of rapamycin complex 1; acute myeloid leukemia; humans; human; article; amino acid transporter; serine/threonine protein kinase wnk1; wnk1 protein, human; wnk lysine-deficient protein kinase 1; induced response; protein serine-threonine kinases; mechanistic target of rapamycin complex 1; stk39 protein, human
Journal Title:	Nature Communications
Volume:	16
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2025-05-27
Start Page:	4920
Language:	English
DOI:	10.1038/s41467-025-59969-8
PUBMED:	40425534
PROVIDER:	scopus
PMCID:	PMC12116911
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105006649305&doi=10.1038%2fs41467-025-59969-8&partnerID=40&md5=297d2699ea78c28965010029c7b34b86
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/226326