A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells.
A novel human protein, ASK (activator of S phase kinase), was identified on the basis of its ability to bind to human Cdc7-related kinase (huCdc7). ASK forms an active kinase complex with huCdc7 that is capable of phosphorylating MCM2 protein. ASK appears to be the major activator of huCdc7, since immunodepletion of ASK protein from the extract is accompanied by the loss of huCdc7-dependent kinase activity. Expression of ASK is regulated by growth factor stimulation, and levels oscillate through the cell cycle, reaching a peak during S phase. Concomitantly, the huCdc7-dependent kinase activity significantly increases when cells are in S phase. Furthermore, we have demonstrated that ASK serves an essential function for entry into S phase by showing that microinjection of ASK-specific antibodies into mammalian cells inhibited DNA replication. Our data show that ASK is a novel cyclin-like regulatory subunit of the huCdc7 kinase complex and that it plays a pivotal role in G1/S transition in mammalian cells.
Kumagai
H
H
Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Japan.
Sato
N
N
Yamada
M
M
Mahony
D
D
Seghezzi
W
W
Lees
E
E
Arai
K
K
Masai
H
H
D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D002455:Cell Division; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004789:Enzyme Activation; D016193:G1 Phase / Q000502:physiology*; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger; D016196:S Phase / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution
D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D011494:Protein Kinases; C068619:CDC7 protein, human; C489403:Cdc7 protein, mouse; D017346:Protein Serine-Threonine Kinases