From a definitional perspective, “metabolic reprogramming” represents “software changes” in cancer cells and describes metabolic alterations that are normally induced by growth factors in proliferating cells but are hijacked by oncogenic signals, whereas “metabolic rewiring” represents “hardware changes” and describes metabolic alterations due to neofunctions of oncogenic mutants, which are not found in normal cells ( 3). The terms metabolic “reprogramming” and “rewiring” have emerged to describe the increasingly better understood metabolic changes observed in cancer cells ( 1, 2). Diverse oncogenic TKs phosphorylate IDH1 WT at Y42 and activate Src to phosphorylate IDH1 at Y391, which contributes to reductive carboxylation and tumor growth, whereas FLT3 or the FLT3-ITD mutation activates JAK2 to enhance mutant IDH1 activity through phosphorylation of Y391 and Y42, respectively, in AML cells. Y391 phosphorylation occurs in both monomeric and dimeric IDH1, which enhances cofactor (NADP + or NADPH) binding. Mechanistically, Y42 phosphorylation occurs in IDH1 monomers, which promotes dimer formation with enhanced substrate (isocitrate or α-ketoglutarate) binding, whereas Y42-phosphorylated dimers show attenuated disruption to monomers. Here, we show that two groups of tyrosine kinases (TK) enhance the activation of mutant and WT IDH1 through preferential Y42 or Y391 phosphorylation. However, the regulatory mechanisms modulating mutant and/or wild-type (WT) IDH1 function remain unknown. Isocitrate dehydrogenase 1 (IDH1) is important for reductive carboxylation in cancer cells, and the IDH1 R132H mutation plays a pathogenic role in cancers including acute myeloid leukemia (AML).
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