TY - JOUR
T1 - Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5
AU - von Kriegsheim, Alex
AU - Pitt, Andrew
AU - Grindlay, G. Joan
AU - Kolch, Walter
AU - Dhillon, Amardeep S.
PY - 2006/9
Y1 - 2006/9
N2 - The 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.
AB - The 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.
UR - http://www.scopus.com/inward/record.url?scp=33748170675&partnerID=8YFLogxK
U2 - 10.1038/ncb1465
DO - 10.1038/ncb1465
M3 - Article
C2 - 16892053
AN - SCOPUS:33748170675
SN - 1465-7392
VL - 8
SP - 1011
EP - 1016
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 9
ER -