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Molecular and Cellular Biology, July 1999, p. 5083-5095, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Novel Growth- and Cell Cycle-Regulated Protein, ASK, Activates Human Cdc7-Related Kinase and Is Essential for G1/S Transition in Mammalian Cells

Hiroyuki Kumagai,1 Noriko Sato,1 Masayuki Yamada,1 Daniel Mahony,2 Wolfgang Seghezzi,2 Emma Lees,2 Ken-Ichi Arai,1,3 and Hisao Masai1,3,*

Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo,1 and CREST, Japan Science and Technology Corporation,3 Tokyo, Japan, and Department of Cell Signaling, DNAX Research Institute, Palo Alto, California2

Received 16 December 1998/Returned for modification 14 January 1999/Accepted 6 April 1999

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.

* Corresponding author. Mailing address: Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5661. Fax: 81-3-5449-5424. E-mail: hisao{at}ims.u-tokyo.ac.jp.

Molecular and Cellular Biology, July 1999, p. 5083-5095, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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