Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions

Jaumot, Montserrat and Hancock, John F. (2001) Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions. Oncogene, 20 30: 3949-3958. doi:10.1038/sj.onc.1204526


Author Jaumot, Montserrat
Hancock, John F.
Title Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
Publication date 2001-06-05
Sub-type Article (original research)
DOI 10.1038/sj.onc.1204526
Volume 20
Issue 30
Start page 3949
End page 3958
Total pages 10
Place of publication London, England
Publisher Nature Publishing Group
Collection year 2001
Language eng
Subject C1
321015 Oncology and Carcinogenesis
730108 Cancer and related disorders
Abstract Raf-1 activation is a complex process which involves plasma membrane recruitment, phosphorylation, protein-protein and lipid-protein interactions, We now show that PP1 and PP2A serine-threonine phosphatases also have a positive role in Ras dependent Raf-1 activation, General serine-threonine phosphatase inhibitors such sodium fluoride, or beta-glycerophosphate and sodium pyrophosphate, or specific PP1 and PP2A inhibitors including microcystin-LR, protein phosphatase 2A inhibitor I-1 or protein phosphatase inhibitor 2 all abrogate H-Ras and K-Ras dependent Raf-1 activation in vitro. A critical Raf-1 target residue for PP1 and PP2A is S259. Serine phosphatase inhibitors block the dephosphorylation of S259, which accompanies Raf-1 activation, and Ras dependent activation of mutant Raf259A is relatively resistant to serine phosphatase inhibitors. Sucrose gradient analysis demonstrates that serine phosphatase inhibition increases the total amount of 14-3-3 and Raf-1 associated with the plasma membrane and significantly alters the distribution of 14-3-3 and Raf-1 across different plasma membrane microdomains, These observations suggest that dephosphorylation of S259 is a critical early step in Ras dependent Raf-1 activation which facilitates 14-3-3 displacement. Inhibition of PP1 and PP2A therefore causes plasma membrane accumulation of Raf-1/14-3-3 complexes which cannot be activated.
Keyword Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
Ras
Raf
14-3-3
Phophatases
Plasma Membrane
Cysteine-rich Domain
Receptor Tyrosine Kinase
Distinct Binding Domains
Plasma-membrane
Signal-transduction
B-raf
Phosphatidylinositol 3-kinase
Oncogenic Ras
Zinc-finger
Phosphorylation
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
 
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Created: Tue, 14 Aug 2007, 15:08:56 EST