c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis

Posted: 2017-01-11   Visits: 53

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.


Source:School of Life Sciences