Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 27, Pages 25388-25395Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M413202200
Keywords
-
Categories
Funding
- NHLBI NIH HHS [R01 HL074948-01A1, HL06078] Funding Source: Medline
- NIGMS NIH HHS [R55 GM056159, GM65160, R01 GM056159-01A2, R01 GM056159, GM56159, R01 GM065160-03, R01 GM065160] Funding Source: Medline
Ask authors/readers for more resources
Recent evidence has implicated the protein phosphatase PP5 in a variety of signaling pathways. Whereas several proteins have been identified that interact with PP5 and regulate its activity, a possibility of its regulation by second messengers remains speculative. Activation of PP5 in vitro by polyunsaturated fatty acids (e. g. arachidonic acid) and fatty acyl-CoA esters (e. g. arachidonoyl-CoA) has been reported. We report here that PP5 is strongly inhibited by micromolar concentrations of a natural polyamine spermine. This inhibition was observed both in assays with a low molecular weight substrate p-nitrophenyl phosphate as well as phosphocasein and apoptosis signal-regulating kinase 1 (ASK1), thought to be a physiological substrate of PP5. Furthermore, a decrease in polyamine levels in COS-7 cells induced by alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, led to accelerated dephosphorylation of oxidative stress-activated ASK1. This effect was suppressed by okadaic acid and by siRNA-mediated PP5 depletion, indicating that the effect of polyamine levels on ASK1 dephosphorylation was mediated by PP5. In line with the decreased ASK1 activation, polyamine depletion in COS-7 cells abrogated oxidative stress-induced activation of caspase-3, which executes ASK1-induced apoptosis, as well as caspase-3 activation induced by ASK1 overexpression, but had no effect on basal caspase-3 activity. These results implicate polyamines, emerging intracellular signaling molecules, as potential physiological regulators of PP5. Our findings also suggest a novel mechanism of the antiapoptotic action of a decrease in polyamine levels via de- inhibition of PP5 and accelerated dephosphorylation and deactivation of ASK1.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available