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Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259

Dhillon, Amardeep, Pollock, C, Steen, H, Shaw, PE, Mischak, H and Kolch, W 2002, Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259, Molecular and Cellular Biology, vol. 22, no. 10, pp. 3237-3246, doi: 10.1128/MCB.22.10.3237-3246.2002.


Title Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259
Author(s) Dhillon, Amardeep
Pollock, C
Steen, H
Shaw, PE
Mischak, H
Kolch, W
Journal name Molecular and Cellular Biology
Volume number 22
Issue number 10
Start page 3237
End page 3246
Total pages 10
Publisher AMER SOC MICROBIOLOGY
Place of publication United States
Publication date 2002-05-09
ISSN 0270-7306
1098-5549
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
SIGNAL-TRANSDUCTION
NEGATIVE REGULATION
14-3-3 PROTEINS
CROSS-TALK
RAS
INHIBITION
ACTIVATION
PATHWAY
IDENTIFICATION
COMPLEXITY
Summary ABSTRACT 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.
Language eng
DOI 10.1128/MCB.22.10.3237-3246.2002
Field of Research 06 Biological Sciences
11 Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30155882

Document type: Journal Article
Collections: Faculty of Health
Open Access Collection
Rural Clinical Schools
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.