ROR2 interacts with JAK1 and JAK2 and potentiates the IFNγ-induced JAK/STAT signaling pathway in colorectal adenocarcinoma

ROR2 interacts with JAK1 and JAK2 and potentiates the IFNγ-induced JAK/STAT signaling pathway in colorectal adenocarcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article ROR2 interacts with JAK1 and JAK2 and potentiates the IFNγ-induced JAK/STAT signaling pathway in colorectal adenocarcinoma Wen-Hui Lien, Juliette de Lhoneux, Martin Veinstein, Zihan Xia, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9532991/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract The Wnt receptor ROR2 is a developmentally critical pseudokinase aberrantly overexpressed in aggressive cancers, where it correlates with poor prognosis and metastasis. However, the molecular mechanisms underlying these pro-tumorigenic effects remain poorly understood. In this study, we profiled the ROR2 interactome in a murine colorectal carcinoma model using co-immunoprecipitation coupled to mass spectrometry, and identified JAK1 and JAK2 as ROR2-binding partners. Functionally, we demonstrated that ROR2 overexpression potentiates the IFNγ-activated JAK/STAT signaling, leading to the upregulation of the immunosuppressive effectors PD-L1 and IDO1. Using computational structural analyses, we identified conserved JAK-binding motifs within the intracellular C-terminal region of ROR2 and demonstrated its functional requirement for IFNγ-JAK/STAT signaling enhancement. Finally, we established the clinical relevance of this ROR2-mediated IFNγ-JAK/STAT axis in human colorectal adenocarcinoma, and showed that high ROR2 expression positively correlates with the IFNγ signature, JAK/STAT signaling, and expression of downstream immunosuppressive effectors. Collectively, our findings uncover a previously unrecognized role for ROR2 as a modulator of a key immune regulatory pathway that drives immune evasion, highlighting ROR2 as a potential therapeutic target. Biological sciences/Cell biology/Cell signalling Biological sciences/Immunology/Tumour immunology/Immunosurveillance Full Text Additional Declarations There is NO conflict of interest to disclose. Supplementary Files SupplementaryTable12.pdf Supplementary Table 1-2 SupplementaryFigureS1S4.pdf Supplementary Figure S1-S4 Cite Share Download PDF Status: Under Review Version 1 posted Reviewer # 1 agreed at journal 10 May, 2026 Reviewers invited by journal 08 May, 2026 Submission checks completed at journal 27 Apr, 2026 Editor assigned by journal 26 Apr, 2026 First submitted to journal 26 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9532991","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":630458735,"identity":"8a2fad83-822b-45cd-8e58-9f9ecd41b3de","order_by":0,"name":"Wen-Hui 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