期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 16, 页码 E1533-E1542出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1303004110
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资金
- Medical Research Council (UK) [G0600765]
- Fondation Leducq [06CVD02]
- Science Foundation Ireland [06/CE/B1129]
- European Union Sixth Framework Programme Specific Targeted Project thera-cAMP [037189]
- Seventh Framework Programme Collaborative Project AffinityProteome [222635]
- National Institutes of Health [NS29740, GM083926]
- Biotechnological and Biological Sciences Research Council (UK) [BB/G020620/1]
- BBSRC [BB/G020620/1] Funding Source: UKRI
- MRC [G0600765] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G020620/1] Funding Source: researchfish
- Medical Research Council [G0600765] Funding Source: researchfish
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.
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