State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Department of Thoracic Surgery, Chenggong Hospital, Xiamen University, Xiamen, Fujian 361003, China.
Nat Commun. 2017 Jan 5;8:13732. 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.
众所周知，c-Src 在肿瘤发生中具有重要作用。然而，c-Src 是否有助于代谢重编程仍不清楚。在这里，我们发现 c-Src 可以与糖酵解限速酶己糖激酶 HK1 和 HK2 相互作用并磷酸化它们。酪氨酸磷酸化显著增加了它们的催化活性，从而增强了糖酵解。在机制上，c-Src 对 HK1 的 Tyr732 残基的磷酸化通过破坏其二聚体形成，显著降低其 K 和增加其 V。HK1 或 HK2 的 c-Src 磷酸化位点的突变显著削弱了 c-Src 对糖酵解、细胞增殖、迁移、侵袭、肿瘤发生和转移的刺激作用。由于其对葡萄糖的 K 值较低，当葡萄糖缺乏时，HK1 而不是 HK2 是肿瘤细胞存活所必需的。重要的是，HK1-Y732 磷酸化水平与各种临床癌症的发病率和转移显著相关，可能作为预测原发性癌症转移风险的标志物。
