SAICAR 诱导 PKM2 的蛋白激酶活性，这对于癌细胞持续的增殖信号传导是必需的。
SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells.
机构信息
Department of Biology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
Department of Biology, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
出版信息
Mol Cell. 2014 Mar 6;53(5):700-9. doi: 10.1016/j.molcel.2014.02.015.
Abnormal metabolism and sustained proliferation are hallmarks of cancer. Pyruvate kinase M2 (PKM2) is a metabolic enzyme that plays important roles in both processes. Recently, PKM2 was shown to have protein kinase activity phosphorylating histone H3 and promoting cancer cell proliferation. However, the mechanism and extent of this protein kinase in cancer cells remain unclear. Here, we report that binding of succinyl-5-aminoimidazole-4-carboxamide-1-ribose-5'-phosphate (SAICAR), a metabolite abundant in proliferating cells, induces PKM2's protein kinase activity in vitro and in cells. Protein microarray experiments revealed that more than 100 human proteins, mostly protein kinases, are phosphorylated by PKM2-SAICAR. In particular, PKM2-SAICAR phosphorylates and activates Erk1/2, which in turn sensitizes PKM2 for SAICAR binding through phosphorylation. Additionally, PKM2-SAICAR was necessary to induce sustained Erk1/2 activation and mitogen-induced cell proliferation. Thus, the ligand-induced protein kinase activity from PKM2 is a mechanism that directly couples cell proliferation with intracellular metabolic status.
异常代谢和持续增殖是癌症的标志。丙酮酸激酶 M2（PKM2）是一种代谢酶，在这两个过程中都发挥着重要作用。最近，PKM2 被证明具有蛋白激酶活性，可磷酸化组蛋白 H3 并促进癌细胞增殖。然而，这种蛋白激酶在癌细胞中的机制和程度尚不清楚。在这里，我们报告说，在体外和细胞中，代谢物琥珀酰-5-氨基咪唑-4-甲酰胺-1-核糖-5′-磷酸（SAICAR）的结合诱导 PKM2 的蛋白激酶活性。蛋白质微阵列实验表明，超过 100 种人类蛋白质，主要是蛋白激酶，被 PKM2-SAICAR 磷酸化。特别是，PKM2-SAICAR 磷酸化并激活 Erk1/2，反过来通过磷酸化使 PKM2 对 SAICAR 结合敏感。此外，PKM2-SAICAR 对于诱导持续的 Erk1/2 激活和有丝分裂原诱导的细胞增殖是必需的。因此，PKM2 配体诱导的蛋白激酶活性是一种将细胞增殖与细胞内代谢状态直接偶联的机制。
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