Nature Cell Biology
- 8, 1011 - 1016 (2006)
Published online: 6 August 2006; | doi:10.1038/ncb1465
Regulation of the Raf–MEK–ERK pathway by protein phosphatase 5Alex von Kriegsheim1, Andrew Pitt2, G. Joan Grindlay1, Walter Kolch1, 2 & Amardeep S. Dhillon11
The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. 2
Sir Henry Wellcome Functional Genomics Facility, University of Glasgow, Glasgow G12 8QQ, UK.
Correspondence should be addressed to Walter Kolch wkolch@beatson.gla.ac.uk or Amardeep S. Dhillon A.Dhillon@beatson.gla.ac.uk Raf-1PP5MEKERKThe Raf–MEK–ERK pathway couples growth factor, mitogenic and extracellular matrix signals to cell fate decisions such as growth, proliferation, migration, differentiation and survival1,
2. Raf-1 is a direct effector of the Ras GTPase and is the initiating kinase in this signalling cascade. Although Raf-1 activation is well studied, little is known about how Raf-1 is inactivated. Here, we used a proteomic approach to identify molecules that may inactivate Raf-1 signalling. Protein phosphatase 5 (PP5) was identified as an inactivator that associates with Raf-1 on growth factor stimulation and selectively dephosphorylates an essential activating site, Ser 338. The PP5-mediated dephosphorylation of Ser 338 inhibited Raf-1 activity and downstream signalling to MEK, an effect that was prevented by phosphomimetic substitution of Ser 338, or by ablation of PP5 catalytic function. Furthermore, depletion of endogenous PP5 increased cellular phospho-Ser 338 levels. Our results suggest that PP5 is a physiological regulator of Raf-1 signalling pathways.
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