{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T20:56:32Z","timestamp":1767992192400,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,7]]},"group-title":"Cancer Biology","reference-count":64,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Oncogenic KRAS and NRAS mutations are common in hematologic malignancies, but how they signal is less well characterized than in carcinomas. To uncover novel RAS biology and potential therapeutic vulnerabilities, we employed a multi-omics screening approach in multiple myeloma to identify regulators of RAS activity. We report that the phosphatase PP1C dephosphorylates the conserved T148 residue on RAS, which in turn permits LZTR1-dependent proteasomal degradation. Notably, LZTR1 is ineffective against KRAS A146 gain-of-function mutations, which are adjacent to T148 and prevalent in hematologic cancers. Remarkably, we find that KRAS protein is four-fold less stable in hematologic versus carcinoma cells, offering a unique therapeutic opportunity targeting RAS protein stability mechanisms. The kinases PAK1 and PAK2 shield RAS from LZTR1-dependent degradation by phosphorylating T148, and targeting PAK1\/2 activity improves RAS-directed therapy. Collectively, our findings reveal a novel regulatory circuit governing RAS stability that is preferentially active in blood cancers and potentially druggable.<\/jats:p>","DOI":"10.64898\/2026.01.07.698128","type":"posted-content","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T07:55:13Z","timestamp":1767858913000},"source":"Crossref","is-referenced-by-count":0,"title":["Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation"],"prefix":"10.64898","author":[{"given":"Lin","family":"Zhang","sequence":"first","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnold","family":"Bolomsky","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar S.","family":"Al-Odat","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Callie","family":"VanWinkle","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaliyah","family":"Battle","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Papiya","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald J.","family":"Holewinski","sequence":"additional","affiliation":[{"name":"Protein Mass Spectrometry Group, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thorkell","family":"Andresson","sequence":"additional","affiliation":[{"name":"Protein Mass Spectrometry Group, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingcai","family":"Meng","sequence":"additional","affiliation":[{"name":"Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James D.","family":"Phelan","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jagan","family":"Muppidi","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan M.","family":"Young","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026010907351077000_2026.01.07.698128v1.1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-3682"},{"key":"2026010907351077000_2026.01.07.698128v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.12.015"},{"key":"2026010907351077000_2026.01.07.698128v1.3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-03-840132"},{"key":"2026010907351077000_2026.01.07.698128v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.142"},{"key":"2026010907351077000_2026.01.07.698128v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrc969"},{"key":"2026010907351077000_2026.01.07.698128v1.6","doi-asserted-by":"crossref","unstructured":"Klomp, J.A. et al. Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers. Science 384, eadk0775 (2024).","DOI":"10.1126\/science.adk0775"},{"key":"2026010907351077000_2026.01.07.698128v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05086-1"},{"key":"2026010907351077000_2026.01.07.698128v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04838-3"},{"key":"2026010907351077000_2026.01.07.698128v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04928-2"},{"key":"2026010907351077000_2026.01.07.698128v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08931-1"},{"key":"2026010907351077000_2026.01.07.698128v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.03.027"},{"key":"2026010907351077000_2026.01.07.698128v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/370527a0"},{"key":"2026010907351077000_2026.01.07.698128v1.13","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1126\/science.adv2684","article-title":"Covalent inhibitors of the PI3Kalpha RAS binding domain impair tumor growth driven by RAS and HER2","volume":"390","year":"2025","journal-title":"Science"},{"key":"2026010907351077000_2026.01.07.698128v1.14","doi-asserted-by":"crossref","first-page":"5469","DOI":"10.1038\/s41467-022-33142-x","article-title":"Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma","volume":"13","year":"2022","journal-title":"Nat Commun"},{"key":"2026010907351077000_2026.01.07.698128v1.15","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2103695"},{"key":"2026010907351077000_2026.01.07.698128v1.16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2204619"},{"key":"2026010907351077000_2026.01.07.698128v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22125-z"},{"key":"2026010907351077000_2026.01.07.698128v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3437"},{"key":"2026010907351077000_2026.01.07.698128v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.05.026"},{"key":"2026010907351077000_2026.01.07.698128v1.20","doi-asserted-by":"publisher","DOI":"10.1042\/BST20200503"},{"key":"2026010907351077000_2026.01.07.698128v1.21","doi-asserted-by":"publisher","DOI":"10.1042\/BST20160154"},{"key":"2026010907351077000_2026.01.07.698128v1.22","doi-asserted-by":"crossref","unstructured":"Chen, M.J. , Dixon, J.E. & Manning, G . Genomics and evolution of protein phosphatases. Sci Signal 10 (2017).","DOI":"10.1126\/scisignal.aag1796"},{"key":"2026010907351077000_2026.01.07.698128v1.23","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-062917-012332"},{"key":"2026010907351077000_2026.01.07.698128v1.24","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E15-12-0844"},{"key":"2026010907351077000_2026.01.07.698128v1.25","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20060678"},{"key":"2026010907351077000_2026.01.07.698128v1.26","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1038\/s43018-024-00784-3","article-title":"The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities","volume":"5","year":"2024","journal-title":"Nat Cancer"},{"key":"2026010907351077000_2026.01.07.698128v1.27","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.1016\/j.apsb.2021.02.014","article-title":"Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators","volume":"11","year":"2021","journal-title":"Acta Pharm Sin B"},{"key":"2026010907351077000_2026.01.07.698128v1.28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1267"},{"key":"2026010907351077000_2026.01.07.698128v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0502-473"},{"key":"2026010907351077000_2026.01.07.698128v1.30","doi-asserted-by":"crossref","first-page":"e0250239","DOI":"10.1371\/journal.pone.0250239","article-title":"Identification of ubiquitination-related genes in human glioma as indicators of patient prognosis","volume":"16","year":"2021","journal-title":"PLoS One"},{"key":"2026010907351077000_2026.01.07.698128v1.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap7607"},{"key":"2026010907351077000_2026.01.07.698128v1.32","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap8210"},{"key":"2026010907351077000_2026.01.07.698128v1.33","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav1444"},{"key":"2026010907351077000_2026.01.07.698128v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"2026010907351077000_2026.01.07.698128v1.35","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1126\/science.adv7088","article-title":"Structural basis for LZTR1 recognition of RAS GTPases for degradation","volume":"389","year":"2025","journal-title":"Science"},{"key":"2026010907351077000_2026.01.07.698128v1.36","doi-asserted-by":"crossref","first-page":"114448","DOI":"10.1016\/j.celrep.2024.114448","article-title":"Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome","volume":"43","year":"2024","journal-title":"Cell Rep"},{"key":"2026010907351077000_2026.01.07.698128v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-024-07487-W"},{"key":"2026010907351077000_2026.01.07.698128v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01853-0"},{"key":"2026010907351077000_2026.01.07.698128v1.39","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-1220"},{"key":"2026010907351077000_2026.01.07.698128v1.40","doi-asserted-by":"crossref","unstructured":"Dempster, J.M. et al. Chronos: a cell population dynamics model of CRISPR experiments that improves inference of gene fitness effects. Genome Biol 22, 343 (2021).","DOI":"10.1186\/s13059-021-02540-7"},{"key":"2026010907351077000_2026.01.07.698128v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1694-1"},{"key":"2026010907351077000_2026.01.07.698128v1.42","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801445"},{"key":"2026010907351077000_2026.01.07.698128v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.015"},{"key":"2026010907351077000_2026.01.07.698128v1.44","doi-asserted-by":"crossref","unstructured":"Alawieh, D. , Cysique-Foinlan, L. , Willekens, C. & Renneville, A . RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives. Blood Cancer J 14, 72 (2024).","DOI":"10.1038\/s41408-024-01054-2"},{"key":"2026010907351077000_2026.01.07.698128v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2103"},{"key":"2026010907351077000_2026.01.07.698128v1.46","doi-asserted-by":"crossref","first-page":"6785","DOI":"10.1016\/j.bmc.2010.07.045","article-title":"Novel indolylmaleimide acts as GSK-3beta inhibitor in human neural progenitor cells","volume":"18","year":"2010","journal-title":"Bioorg Med Chem"},{"key":"2026010907351077000_2026.01.07.698128v1.47","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0027"},{"key":"2026010907351077000_2026.01.07.698128v1.48","doi-asserted-by":"crossref","unstructured":"Jeong, W.J. et al. Ras stabilization through aberrant activation of Wnt\/beta-catenin signaling promotes intestinal tumorigenesis. Sci Signal 5, ra30 (2012).","DOI":"10.1126\/scisignal.2002242"},{"key":"2026010907351077000_2026.01.07.698128v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00122-7"},{"key":"2026010907351077000_2026.01.07.698128v1.50","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M509073200"},{"key":"2026010907351077000_2026.01.07.698128v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2008.10.016"},{"key":"2026010907351077000_2026.01.07.698128v1.52","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-16-0369"},{"key":"2026010907351077000_2026.01.07.698128v1.53","doi-asserted-by":"crossref","first-page":"13362","DOI":"10.1021\/acsomega.3c00804","article-title":"In Silico Analysis of nsSNPs of Human KRAS Gene and Protein Modeling Using Bioinformatic Tools","volume":"8","year":"2023","journal-title":"ACS Omega"},{"key":"2026010907351077000_2026.01.07.698128v1.54","doi-asserted-by":"crossref","unstructured":"Kwon, J.J. et al. Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity. bioRxiv, 2024.2010.2022.618529 (2024).","DOI":"10.1101\/2024.10.22.618529"},{"key":"2026010907351077000_2026.01.07.698128v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(97)70091-5"},{"key":"2026010907351077000_2026.01.07.698128v1.56","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2014-306768"},{"key":"2026010907351077000_2026.01.07.698128v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/nature09837"},{"key":"2026010907351077000_2026.01.07.698128v1.58","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9151-8_16"},{"key":"2026010907351077000_2026.01.07.698128v1.59","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026010907351077000_2026.01.07.698128v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0290-0"},{"key":"2026010907351077000_2026.01.07.698128v1.61","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"2026010907351077000_2026.01.07.698128v1.62","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp427"},{"key":"2026010907351077000_2026.01.07.698128v1.63","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad350"},{"key":"2026010907351077000_2026.01.07.698128v1.64","doi-asserted-by":"publisher","DOI":"10.1002\/PRO.3943"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.07.698128","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T15:35:20Z","timestamp":1767972920000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.07.698128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,7]]},"references-count":64,"URL":"https:\/\/doi.org\/10.64898\/2026.01.07.698128","relation":{},"subject":[],"published":{"date-parts":[[2026,1,7]]},"subtype":"preprint"}}