{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T18:12:32Z","timestamp":1760551952136,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["5U54MD007592","R25GM069621-18"],"award-info":[{"award-number":["5U54MD007592","R25GM069621-18"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["5U54MD007592","R25GM069621-18"],"award-info":[{"award-number":["5U54MD007592","R25GM069621-18"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Overactive Janus kinases (JAKs) are known to drive leukemia, making them well-suited targets for treatment. We sought to identify new JAK-activating mutations and instead found a JAK1-inactivating pseudokinase mutation, V666G. In contrast to other pseudokinase mutations that canonically lead to an active kinase, the JAK1 V666G mutation led to under-activation seen by reduced phosphorylation. To understand the functional role of JAK1 V666G in modifying kinase activity we investigated its influence on other JAK kinases and within the Interleukin-2 pathway. JAK1 V666G not only inhibited its own activity, but its presence could inhibit other JAK kinases. These findings provide new insights into the potential of JAK1 pseudokinase to modulate its own activity, as well as of other JAK kinases. Thus, the features of the JAK1 V666 region in modifying JAK kinases can be exploited to allosterically inhibit overactive JAKs.<\/jats:p>","DOI":"10.3390\/ijms24076805","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T02:29:58Z","timestamp":1680748198000},"page":"6805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["JAK1 Pseudokinase V666G Mutant Dominantly Impairs JAK3 Phosphorylation and IL-2 Signaling"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1124-5818","authenticated-orcid":false,"given":"Alice H.","family":"Grant","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6409-3088","authenticated-orcid":false,"given":"Alejandro C.","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar J.","family":"Rodriguez Moncivais","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengjie","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physics, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Computational Science Program, The University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6447-2398","authenticated-orcid":false,"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Physics, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Computational Science Program, The University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4440-4608","authenticated-orcid":false,"given":"Jonathon E.","family":"Mohl","sequence":"additional","affiliation":[{"name":"Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Department of Mathematical Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2035-1214","authenticated-orcid":false,"given":"Ming-Ying","family":"Leung","sequence":"additional","affiliation":[{"name":"Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Computational Science Program, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Department of Mathematical Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Kirken","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgialina","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA"},{"name":"Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.4049\/jimmunol.178.5.2623","article-title":"The JAK-STAT signaling pathway: Input and output integration","volume":"178","author":"Murray","year":"2007","journal-title":"J. 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