c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis.
c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis.
复制标题
c-Src磷酸化和己糖激酶激活促进肿瘤发生和转移
DOI：
10.1038/ncomms13732
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发表时间：
2017-01-05
影响因子：
16.6
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Zhang J;Wang S;Jiang B;Huang L;Ji Z;Li X;Zhou H;Han A;Chen A;Wu Y;Ma H;Zhao W;Zhao Q;Xie C;Sun X;Zhou Y;Huang H;Suleman M;Lin F;Zhou L;Tian F;Jin M;Cai Y;Zhang N;Li Q
众所周知，c-Src在肿瘤发生中起着重要作用。然而，尚不清楚c-Src是否有助于代谢重编程。在这里，我们发现c-Src可以与糖酵解中的限速酶HK1和HK2相互作用并使其磷酸化。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。机制上，c-Src对HK1 Tyr732位点的磷酸化通过破坏其二聚体的形成而显著降低其K - m并增加其V - max。HK1或HK2的c-Src磷酸化位点发生突变，可显著消除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。由于葡萄糖的K - m较低，当葡萄糖缺乏时，肿瘤细胞存活需要HK1而不是HK2。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，并可能作为预测原发癌症转移风险的标志。
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 m and increases its V max 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 m 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.