Suzuki Atsushi, Kusakai Gen-Ichi, Kishimoto Atsuhiro, Lu Jie, Ogura Tsutomu, Lavin Martin F, Esumi Hiroyasu
Investigative Treatment Division, National Cancer Center Research Institute East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
J Biol Chem. 2003 Jan 3;278(1):48-53. doi: 10.1074/jbc.M206025200. Epub 2002 Oct 29.
We identified a novel human AMP-activated protein kinase (AMPK) family member, designated ARK5, encoding 661 amino acids with an estimated molecular mass of 74 kDa. The putative amino acid sequence reveals 47, 45.8, 42.4, and 55% homology to AMPK-alpha1, AMPK-alpha2, MELK, and SNARK, respectively, suggesting that it is a new member of the AMPK family. It has a putative Akt phosphorylation motif at amino acids 595-600, and Ser(600) was found to be phosphorylated by active Akt resulting in the activation of kinase activity toward the SAMS peptide, a consensus AMPK substrate. During nutrient starvation, ARK5 supported the survival of cells in an Akt-dependent manner. In addition, we also demonstrated that ARK5, when activated by Akt, phosphorylated the ATM protein that is mutated in the human genetic disorder ataxia-telangiectasia and also induced the phosphorylation of p53. On the basis of our current findings, we propose that a novel AMPK family member, ARK5, is the tumor cell survival factor activated by Akt and acts as an ATM kinase under the conditions of nutrient starvation.
我们鉴定出一种新的人类AMP活化蛋白激酶（AMPK）家族成员，命名为ARK5，它编码661个氨基酸，估计分子量为74 kDa。推测的氨基酸序列分别与AMPK-α1、AMPK-α2、MELK和SNARK有47%、45.8%、42.4%和55%的同源性，表明它是AMPK家族的一个新成员。它在氨基酸595 - 600处有一个推测的Akt磷酸化基序，并且发现Ser(600) 被活性Akt磷酸化，从而导致对一致的AMPK底物SAMS肽的激酶活性激活。在营养饥饿期间，ARK5以Akt依赖的方式支持细胞存活。此外，我们还证明，当ARK5被Akt激活时，它会磷酸化在人类遗传性疾病共济失调 - 毛细血管扩张症中发生突变的ATM蛋白，并且还会诱导p53的磷酸化。基于我们目前的发现，我们提出一种新的AMPK家族成员ARK5是由Akt激活的肿瘤细胞存活因子，并且在营养饥饿条件下起ATM激酶的作用。
