Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein.
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.
Suzuki
Atsushi
A
Investigative Treatment Division, National Cancer Center Research Institute East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
Kusakai
Gen-Ichi
G
Kishimoto
Atsuhiro
A
Lu
Jie
J
Ogura
Tsutomu
T
Lavin
Martin F
MF
Esumi
Hiroyasu
H
D055372:AMP-Activated Protein Kinases; D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D012694:Serine; D011494:Protein Kinases; C470845:NUAK1 protein, human; C494918:AKT1 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C486061:NUAK2 protein, human; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human