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Molecular and Cellular Biology, May 2002, p. 3237-3246, Vol. 22, No. 10
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.10.3237-3246.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cyclic AMP-Dependent Kinase Regulates Raf-1 Kinase Mainly by Phosphorylation of Serine 259

Amardeep S. Dhillon,1 Claire Pollock,1 Helge Steen,2,{dagger} Peter E. Shaw,2 Harald Mischak,3 and Walter Kolch1,4*

The Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD,1 School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH,2 Institute for Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom,4 Department of Nephrology, Medizinische Hochschule Hannover, 30625 Hannover, Germany3

Received 27 July 2001/ Returned for modification 19 September 2001/ Accepted 8 February 2002

The Raf-1 kinase activates the ERK (extracellular-signal-regulated kinase) pathway. The cyclic AMP (cAMP)-dependent protein kinase (PKA) can inhibit Raf-1 by direct phosphorylation. We have mapped all cAMP-induced phosphorylation sites in Raf-1, showing that serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo. Serine 43 phosphorylation decreased the binding to Ras in serum-starved but not in mitogen-stimulated cells. However, the kinase activity of a RafS43A mutant was fully inhibited by PKA. Mutation of serine 259 increased the basal Raf-1 activity and rendered it largely resistant to inhibition by PKA. cAMP increased Raf-1 serine 259 phosphorylation in a PKA-dependent manner with kinetics that correlated with ERK deactivation. PKA also decreased Raf-1 serine 338 phosphorylation of Raf-1, previously shown to be required for Raf-1 activation. Serine 338 phosphorylation of a RafS259A mutant was unaffected by PKA. Using RafS259 mutants we also demonstrate that Raf-1 is the sole target for PKA inhibition of ERK and ERK-induced gene expression, and that Raf-1 inhibition is mediated mainly through serine 259 phosphorylation.

* Corresponding author. Mailing address: CRC Beatson Laboratories, Switchback Rd., Garscube Estate, Glasgow G61 1BD, United Kingdom. Phone: 0044-141-330 3983. Fax: 0044-141-942 6521. E-mail: wkolch{at}beatson.gla.ac.uk.

{dagger} Present address: BioChip Technologies GmbH, GeneScan Europe AG, D-79108 Freiburg, Germany.

Molecular and Cellular Biology, May 2002, p. 3237-3246, Vol. 22, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.10.3237-3246.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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