---
title: "Tyrosine Phosphorylation and Dimerization Activate NAMPT to Drive NAD+ Synthesis in Cancer"
id: "biorxiv-4-tyrosine-phosphorylation-and-dimerization-cooperatively-activate-nampt-to"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-4-tyrosine-phosphorylation-and-dimerization-cooperatively-activate-nampt-to"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.13.744642v1?rss=1"
published_at: "2026-08-15T10:16:12.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Tyrosine Phosphorylation and Dimerization Activate NAMPT to Drive NAD+ Synthesis in Cancer
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-4-tyrosine-phosphorylation-and-dimerization-cooperatively-activate-nampt-to
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.13.744642v1?rss=1)
- **Published At:** 2026-08-15T10:16:12.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study identifies **NAMPT** as a direct substrate of multiple proto-oncogenic **tyrosine kinases** including ALK, insulin receptor, IGF1R, and PDGFRA, with phosphorylation enhancing its catalytic function. - Phosphoproteomics pinpointed **Y188** as the major phosphorylation site on NAMPT, observed with oncogenic fusion kinase **NPM1::ALK** among others. - NAMPT physically interacts with NPM1::ALK in the cytoplasm, nucleus, and mitochondria; Y188 phosphorylation increases enzymatic activity and promotes **NMN/NAD+ biosynthesis** and downstream metabolic changes. - A Y188F NAMPT mutant showed reduced enzymatic activity, cell proliferation, and clonogenic potential, indicating the functional importance of this phosphorylation site. - Disrupting **dimerization** of NAMPT impaired both its phosphorylation and enzymatic function, demonstrating cooperative roles for phosphorylation and dimer formation. - Interactome analyses revealed that phosphorylated, dimeric NAMPT associates preferentially with metabolic and redox regulators, while monomeric NAMPT associates more with ribosome biogenesis factors. - Pharmacologic NAMPT inhibition suppressed growth of ALK inhibitor–sensitive and –resistant lymphoma cells and enhanced the efficacy of ALK inhibition, highlighting kinase-dependent NAMPT activation as a metabolic vulnerability in oncogene-driven cancers. - The authors note competing interests related to patents and industry funding for some investigators; research funders did not influence study design or reporting. - The preprint was posted on bioRxiv on August 15, 2026. Details on experimental protocols, quantitative effect sizes, and specific inhibitor names or concentrations were not reported in the abstract.
## Clinical Analysis & Structured Key Points
Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer | bioRxiv Skip to main content New Results Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer View ORCID Profile Johnvesly Basappa , Cosimo Lobello , Anneliese M Faustino , Cristina Uribe-Alvarez , David Rushmore , Neil Sen , Li Wang , Andrey Efimov , Kathy Q Cai , Jaime L Schneider , Lori Rink , Aaron N Hata , Luca Mologni , Wujuan Zhang , Aaron R Goldman , Hsin-Yao Tang , Reza Nejati , Roland Dunbrack , Jonathan Chernoff , Joseph A Baur , Mariusz A Wasik doi: https://doi.org/10.64898/2026.08.13.744642 Johnvesly Basappa 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Johnvesly Basappa For correspondence: johnvesly.basappa{at}fccc.edu Cosimo Lobello 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anneliese M Faustino 2 The Wistar Institute, Philadelphia, PA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Cristina Uribe-Alvarez 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site David Rushmore 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Neil Sen 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Li Wang 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrey Efimov 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kathy Q Cai 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jaime L Schneider 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lori Rink 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Aaron N Hata 4 Department of Medicine, Massachusetts General Hospital, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Luca Mologni 5 Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Wujuan Zhang 2 The Wistar Institute, Philadelphia, PA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Aaron R Goldman 2 The Wistar Institute, Philadelphia, PA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hsin-Yao Tang 2 The Wistar Institute, Philadelphia, PA, USA; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Reza Nejati 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Roland Dunbrack 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jonathan Chernoff 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joseph A Baur 6 Institute for Diabetes, Obesity and Metabolism and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mariusz A Wasik 1 Fox Chase Cancer Center; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Info/History Metrics Preview PDF Abstract Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage pathway, is frequently upregulated in cancer, yet mechanisms regulating its catalytic activity remain undefined. We identify NAMPT as a direct substrate of multiple proto-oncogenic tyrosine kinases, including ALK, insulin receptor, IGF1R, and PDGFRA. Phosphoproteomics identified NAMPT Y188 as the major phosphorylation site, including the oncogenic fusion kinase NPM1::ALK. NAMPT interacted with NPM1::ALK in the cytoplasm, nucleus, and mitochondria, while Y188 phosphorylation enhanced catalytic activity, NMN/NAD⁺ biosynthesis, and downstream metabolism. Conversely, the Y188F mutant reduced enzymatic activity, proliferation, and clonogenicity, whereas disrupting dimerization similarly impaired phosphorylation and function. Interactome analyses showed phosphorylation and dimerization cooperatively remodel NAMPT-associated networks, enriching phosphorylated dimers for metabolic/redox regulators and monomeric NAMPT for ribosome biogenesis. NAMPT inhibition suppressed the growth of both ALK inhibitor-sensitive and -resistant lymphoma cells and enhanced the efficacy of ALK inhibition, revealing kinase-dependent NAMPT activation as a metabolic vulnerability in oncogene-driven cancers. Competing Interest Statement J.B. and M.W. are inventors on a patent (No. 63/870,711; Treatment of Nicotinamide Phosphoribosyltransferase (NAMPT) Related Diseases). J.A.B. has received research funding and materials from Pfizer, Elysium Health and Metro International Biotech and consulting fees from Pfizer, Elysium Health, Cytokinetics, and Altimmune and is an inventor on a patent (No. 16/078,446; Methods for Enhancing Liver Regeneration for the use of NAD precursors to promote liver regeneration. The remaining authors declare no competing interests. Research funding agencies played no role in the conceptualization, design, data collection, analysis, decision to publish or preparation of this manuscript. A.N.H. has received research funding from Amgen, BridgeBio Oncology Therapeutics, Bristol Myers Squibb, Eli Lilly, Immuto Scientific, Novartis, Nuvalent, Pfizer, Scorpion Therapeutics, Triana Biomedicines; consulting fees from Nuvalent. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Back to top Previous Next Posted August 15, 2026. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer Johnvesly Basappa , Cosimo Lobello , Anneliese M Faustino , Cristina Uribe-Alvarez , David Rushmore , Neil Sen , Li Wang , Andrey Efimov , Kathy Q Cai , Jaime L Schneider , Lori Rink , Aaron N Hata , Luca Mologni , Wujuan Zhang , Aaron R Goldman , Hsin-Yao Tang , Reza Nejati , Roland Dunbrack , Jonathan Chernoff , Joseph A Baur , Mariusz A Wasik bioRxiv 2026.08.13.744642; doi: https://doi.org/10.64898/2026.08.13.744642 Share This Article: Copy Citation Tools Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer Johnvesly Basappa , Cosimo Lobello , Anneliese M Faustino , Cristina Uribe-Alvarez , David Rushmore , Neil Sen , Li Wang , Andrey Efimov , Kathy Q Cai , Jaime L Schneider , Lori Rink , Aaron N Hata , Luca Mologni , Wujuan Zhang , Aaron R Goldman , Hsin-Yao Tang , Reza Nejati , Roland Dunbrack , Jonathan Chernoff , Joseph A Baur , Mariusz A Wasik bioRxiv 2026.08.13.744642; doi: https://doi.org/10.64898/2026.08.13.744642 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (7889) Biochemistry (18462) Bioengineering (14617) Bioinformatics (43674) Biophysics (22229) Cancer Biology (19366) Cell Biology (26493) Clinical Trials (138) Developmental Biology (13786) Ecology (20667) Epidemiology (2067) Evolutionary Biology (25118) Genetics (15993) Genomics (23233) Immunology (18408) Microbiology (41865) Molecular Biology (17778) Neuroscience (91983) Paleontology (688) Pathology (2940) Pharmacology and Toxicology (5015) Physiology (7982) Plant Biology (15724) Scientific Communication and Education (2082) Synthetic Biology (4489) Systems Biology (10105) Zoology (2353)
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