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

• Published in: Nature communications Vol. 8; no. 1; p. 13732
• Main Authors: Zhang, Jia, Wang, Suili, Jiang, Bin, Huang, Lihong, Ji, Zhiliang, Li, Xiaotong, Zhou, Huamin, Han, Aidong, Chen, Ai, Wu, Yanan, Ma, Huanhuan, Zhao, Wentao, Zhao, Qingwen, Xie, Changchuan, Sun, Xiaoyan, Zhou, Yanming, Huang, Huiying, Suleman, Muhammad, Lin, Furong, Zhou, Lin, Tian, Fang, Jin, Meijun, Cai, Yana, Zhang, Nan, Li, Qinxi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 05.01.2017; Nature Portfolio
• Subjects: Animals; Antibodies; Cancer; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Enzyme Activation; Enzymes; Glucose; Glucose - metabolism; Glucose-6-Phosphate - metabolism; Glycolysis; Growth factors; Heterografts; Hexokinase - metabolism; Humans; Kinases; Kinetics; Male; Metabolic Networks and Pathways; Metabolism; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neoplasms - pathology; Phosphorylation; Protein Binding; Proteins; Proto-Oncogene Proteins pp60(c-src) - metabolism; Thoracic surgery; Tumorigenesis; Tyrosine - metabolism; China
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13732

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 K and increases its V 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 K 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.