A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G(1)/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). AS K forms an active kinase complex with huCdc7 that is capable of phosphoryla ting MCM2 protein. ASK appears to be the major activator of huCdc7, since i mmunodepletion of ASK protein from the extract is accompanied by the loss o f huCdc7-dependent kinase activity. Expression of ASK is regulated by growt h 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 de monstrated 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 r egulatory subunit of the huCdc7 kinase complex and that it plays a pivotal role in G(1)/S transition in mammalian cells.