Visit our Expo - Redox and Inflammation signaling 2012

Session III : Protein kinase cascades as therapeutic targets Poster III, 19
The ERK5 pathway promotes cell survival by down-regulating FasL expression
following osmotic stress stimulation
Katherine G Finegan1, Xin Wang1, Andrew C. Robinson1, Lynette Knowles1, Roya
Khosravi-Far2, Katherine A. Hinchliffe1, Raymond P. Boot-Handford3 and Cathy
Tournier1
Faculty of Life Sciences1 and Wellcome Trust Center for Cell Matrix3, University of
Manchester, Michael Smith Building, Oxford Road Manchester M130PT, UK;
Deparment of Pathology2, Harvard Medical School, Boston MA 02215, USA
Extracellular signal-regulated kinase 5 (ERK5) is a mitogen-activated protein kinase (MAPK)
that is activated by dual phosphorylation via a unique MAPK/ERK kinase, MEK5. The
analysis of the targeted deletion of the erk5 and mek5 genes has demonstrated a physiological
significance in their role in promoting cell survival. We have identified how the ERK5
signalling pathway regulates this process using as our models fibroblasts deficient in either
ERK5 or MEK5 expression. We found that ERK5 was required for mediating the survival of
fibroblasts under basal conditions and in response to sorbitol treatment. Increased FasL
expression acted in a positive feedback loop to enhance apoptosis of ERK5- or MEK5deficient
cells under conditions of osmotic stress. Compared to wild type cells, erk5-/- and
mek5-/- fibroblasts treated with sorbitol displayed a reduced Protein Kinase B (PKB) activity
associated with increased Foxo3a activity. Based on these results we conclude that the ERK5
signalling pathway promotes cell survival by down-regulating FasL expression via a
mechanism that implicates PKB-dependent inhibition of Foxo3a downstream of
Phosphatidylinositol 3-Kinase.
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