Phosphodiesterase-8A binds to and regulates Raf-1 kinase

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Title: Phosphodiesterase-8A binds to and regulates Raf-1 kinase
Authors: Brown, K. M.
Day, J. P.
Huston, E.
et al.
Permanent link: http://hdl.handle.net/10197/5062
Date: 18-Mar-2013
Abstract: V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) is a key activator of the ERK pathway and is a target for cross-regulation of this pathway by the cAMP signaling system. The cAMP-activated protein kinase, PKA, inhibits Raf-1 by phosphorylation on S259. Here, we show that the cAMP-degrading phosphodiesterase-8A (PDE8A) associates with Raf-1 to protect it from inhibitory phosphorylation by PKA, thereby enhancing Raf-1’s ability to stimulate ERK signaling. PDE8A binds to Raf-1 with high (picomolar) affinity. Mapping of the interaction domain on PDE8A using peptide array technology identified amino acids 454–465 as the main binding site, which could be disrupted by mutation. A cell-permeable peptide corresponding to this region disrupted the PDE8A/Raf-1 interaction in cells, thereby reducing ERK activation and the cellular response to EGF. Overexpression of a catalytically inactive PDE8A in cells displayed a dominant negative phenotype on ERK activation. These effects were recapitulated at the organism level in genetically modified (PDE8A−/−) mice. Similarly, PDE8 deletion in Drosophila melanogaster reduced basal ERK activation and sensitized flies to stress-induced death. We propose that PDE8A is a physiological regulator of Raf-1 signaling in some cells.
Type of material: Journal Article
Publisher: Proceedings of the National Academy of Sciences
Copyright (published version): 2013 Proceedings of the National Academy of Sciences
Keywords: phosphodiesterase-8A (PDE8A);Raf-1 kinase
DOI: 10.1073/pnas.1303004110
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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