Abstract
It is well known that c-Src has important roles in tumorigenesis. However, it remains unclear whether c-Src contributes to metabolic reprogramming. Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate-limiting enzymes in glycolysis. Tyrosine phosphorylation dramatically increases their catalytic activity and thus enhances glycolysis. Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation. Mutation in c-Src phosphorylation site of either HK1 or HK2 remarkably abrogates the stimulating effects of c-Src on glycolysis, cell proliferation, migration, invasion, tumorigenesis and metastasis. Due to its lower Km for glucose, HK1 rather than HK2 is required for tumour cell survival when glucose is scarce. Importantly, HK1-Y732 phosphorylation level remarkably correlates with the incidence and metastasis of various clinical cancers and may serve as a marker to predict metastasis risk of primary cancers.
Highlights
It is well known that c-Src has important roles in tumorigenesis
Increased protein levels and/or constitutive activation of c-Src were observed in human cancers originating from a wide spectrum of tissues including colon, breast, lung, liver, pancreas and prostate, implying that uncontrollable activation of c-Src is involved in tumorigenesis and/or metastasis in some of these tumours[3,5]
The bestcharacterized metabolic reprogramming in cancer cells is Warburg effect, which is described as a shift of ATP generation from through oxidative phosphorylation to through glycolysis even under non-hypoxia condition[7]
Summary
It is well known that c-Src has important roles in tumorigenesis It remains unclear whether c-Src contributes to metabolic reprogramming. Mutation in c-Src phosphorylation site of either HK1 or HK2 remarkably abrogates the stimulating effects of c-Src on glycolysis, cell proliferation, migration, invasion, tumorigenesis and metastasis. Increased protein levels and/or constitutive activation of c-Src were observed in human cancers originating from a wide spectrum of tissues including colon, breast, lung, liver, pancreas and prostate, implying that uncontrollable activation of c-Src is involved in tumorigenesis and/or metastasis in some of these tumours[3,5]. The bestcharacterized metabolic reprogramming in cancer cells is Warburg effect, which is described as a shift of ATP generation from through oxidative phosphorylation to through glycolysis even under non-hypoxia condition[7]. Substitution of cellular HK1 or HK2 with their corresponding mutants significantly diminishes c-Src stimulated glucose uptake, retarded proliferation and dampened xenograft tumour growth in nude mice
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