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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\u207a 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.<\/jats:p>","DOI":"10.64898\/2026.08.13.744642","type":"posted-content","created":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T09:20:13Z","timestamp":1786785613000},"source":"Crossref","is-referenced-by-count":0,"title":["Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0907-3541","authenticated-orcid":false,"given":"Johnvesly","family":"Basappa","sequence":"first","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosimo","family":"Lobello","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, 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