Rath, O., Park, S., Tang, H.H., Banfield, M.J., Brady, R.L., Lee, Y.C., Dignam, J.D., Sedivy, J.M., Kolch, W. and Yeung, K.C. (2008) The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated activated phosphorylation of MEK. Cellular Signalling, 20(5), pp. 935-941. (doi: 10.1016/j.cellsig.2008.01.012)
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Publisher's URL: http://dx.doi.org/10.1016/j.cellsig.2008.01.012
Abstract
The Raf-MEK-ERK pathway regulates many fundamental biological processes, and its activity is finely tuned at multiple levels. The Raf kinase inhibitory protein (RKIP) is a widely expressed negative modulator of the Raf-MEK-ERK signaling pathway. We have previously shown that RKIP inhibits the phosphorylation of MEK by Raf-1 through interfering with the formation of a kinase-substrate complex by direct binding to both Raf-1 and MEK. Here, we show that the evolutionarily conserved ligand-binding pocket of RKIP is required for its inhibitory activity towards the Raf-1 kinase mediated activation of MEK. Single amino acid substitutions of two of the conserved residues form the base and the wall of the pocket confers a loss-of-function phenotype on RKIP. Loss-of-function RKIP mutants still appear to bind to Raf-1. However the stability of the complexes formed between mutants and the N-region Raf-1 phosphopeptide were drastically reduced. Our results therefore suggest that the RKIP conserved pocket may constitute a novel phosphoamino-acid binding motif and is absolutely required for RKIP function. (C) 2008 Elsevier Inc. All rights reserved
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Kolch, Prof Walter |
Authors: | Rath, O., Park, S., Tang, H.H., Banfield, M.J., Brady, R.L., Lee, Y.C., Dignam, J.D., Sedivy, J.M., Kolch, W., and Yeung, K.C. |
Subjects: | Q Science > QH Natural history > QH345 Biochemistry |
College/School: | College of Medical Veterinary and Life Sciences |
Journal Name: | Cellular Signalling |
ISSN: | 0898-6568 |
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