Abstract
Reactive oxygen species (ROS) are not only harmful to cell survival but also essential to cell signaling through cysteine-based redox switches. In fact, ROS triggers the potential activation of mitogen-activated protein kinases (MAPKs). The 90 kDa ribosomal S6 kinase 1 (RSK1), one of the downstream mediators of the MAPK pathway, is implicated in various cellular processes through phosphorylating different substrates. As such, RSK1 associates with and phosphorylates neuronal nitric oxide (NO) synthase (nNOS) at Ser847, leading to a decrease in NO generation. In addition, the RSK1 activity is sensitive to inhibition by reversible cysteine-based redox modification of its Cys223 during oxidative stress. Aside from oxidative stress, nitrosative stress also contributes to cysteine-based redox modification. Thus, the protein kinases such as Ca2+/calmodulin (CaM)-dependent protein kinase I (CaMKI) and II (CaMKII) that phosphorylate nNOS could be potentially regulated by cysteine-based redox modification. In this review, we focus on the role of post-translational modifications in regulating nNOS and nNOS-phosphorylating protein kinases and communication among themselves.
Highlights
The mitogen-activated protein kinases (MAPKs) are a highly conserved family of serine/threonine kinases that play a central role in the range of fundamental cellular processes like cell growth, proliferation, death, and differentiation [1]
We propose here the phosphorylation- and NOS-signaling are mutually regulated via phospho-nitric oxide (NO) synthase (nNOS) at Ser741/S-glutathionylated CaMKI at Cys179 and phospho-nNOS at Ser847/ S-glutathionylated ribosomal S6 kinase 1 (RSK1) at Cys223 and S-nitrosylated CaMKII at Cys6/30
CaMKIV is localized predominantly in the nucleus and cannot phosphorylate nNOS which is not present in the nucleus and might not be sensitive to nitrosative stress. It is not clear how nNOS-phosphorylating protein kinases as CaMKI, CaMKII, and RSK1 are regulated by the specific type of redox-sensitive Cys modification in pathophysiological response in cells
Summary
The mitogen-activated protein kinases (MAPKs) are a highly conserved family of serine/threonine kinases that play a central role in the range of fundamental cellular processes like cell growth, proliferation, death, and differentiation [1]. MAPK activation regulates docking interactions with MAPKAPKs, a phenomenon that was first described for the interaction between ERK1/2 and 90 kDa ribosomal S6 kinases (RSKs) family members [3]. RSKs are activated by ERK1/2 [5] and 3-phosphoinositide-dependent protein kinase 1 (PDK1) [6] by sequential phosphorylation in the C-terminal kinase domain (CTKD). 2 of 17 2 of 16 protein kinase 1 (PDK1) [6] by sequential phosphorylation in the C-terminal kinase domain (CTKD) at TathrT5h7r357a3ndanthdethNe-tNer-mterinmailnkailnkaisneadseomdoamina(iNn T(NKTDK) Dat) SaetrS2e2r12[271],[7re],spreescptievcetliyve(lFyig(Fuirgeu1r)e. 2 of 17 2 of 16 protein kinase 1 (PDK1) [6] by sequential phosphorylation in the C-terminal kinase domain (CTKD) at TathrT5h7r357a3ndanthdethNe-tNer-mterinmailnkailnkaisneadseomdoamina(iNn T(NKTDK) Dat) SaetrS2e2r12[271],[7re],spreescptievcetliyve(lFyig(Fuirgeu1r)e. 1W).hWenhen actaivcatitveadt,edR,SRKSpKropmroomteostethsethpehopshpohsoprhyolraytiloatnioonf omfamnyancyytcoystoolsicolaicndannducnluecalreatarrgtaertgsetthsatthraetgruelgautelate divdeirvseercseellcuellalurlparropcreoscseesss, eins,cilnucdliundgincegllcgelrlogwrothw, tphr,oplirfoelriafteiroanti,osnu,rsvuivrvali,vaanl,danmdotmiloittyil[it8y].[8]
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