Antagonistic roles for STYX pseudophosphatases in neurite outgrowth

2017 ◽  
Vol 45 (2) ◽  
pp. 381-387 ◽  
Author(s):  
Arya Dahal ◽  
Shantá D. Hinton

Mitogen-activated protein kinases (MAPKs) are essential players in important neuronal signaling pathways including neuronal development, plasticity, survival, learning, and memory. The inactivation of MAPKs is tightly controlled by MAPK phosphatases (MKPs), which also are important regulators of these neuronal processes. Considering that MAPKs and MKPs are major players in neuronal signaling, it follows that their misregulation is pivotal in neurodegenerative diseases such as Alzheimer's, Huntington's, Parkinson's, and amyotrophic lateral sclerosis. In contrast, the actions of their noncatalytic homologs, or pseudoenzymes, have received minimal attention as important regulators in neuronal signaling pathways and relevant diseases. There is compelling evidence, however, that pseudophosphatases, such as STYX (phospho-serine–threonine/tyrosine-binding protein) and MAPK-STYX (MK-STYX), are integral signaling molecules in regulating pathways involved in neuronal developmental processes such as neurite outgrowth. Here, we discuss how the dynamics of MK-STYX in the stress response pathway imply that this unique member of the MKP subfamily has the potential to have a major role in neuronal signaling. We further compare the actions of STYX in preventing neurite-like outgrowths and MK-STYX in inducing neurite outgrowths. The roles of these pseudophosphatases in neurite outgrowth highlight their emergence as important candidates to investigate in neurodegenerative disorders and diseases.

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 581
Author(s):  
Lihong Cheng ◽  
Hiroyuki Osada ◽  
Tianyan Xing ◽  
Minoru Yoshida ◽  
Lan Xiang ◽  
...  

Amarogentin (AMA) is a secoiridoid glycoside isolated from the traditional Chinese medicine, Gentiana rigescens Franch. AMA exhibits nerve growth factor (NGF)-mimicking and NGF-enhancing activities in PC12 cells and in primary cortical neuron cells. In this study, a possible mechanism was found showing the remarkable induction of phosphorylation of the insulin receptor (INSR) and protein kinase B (AKT). The potential target of AMA was predicted by using a small-interfering RNA (siRNA) and the cellular thermal shift assay (CETSA). The AMA-induced neurite outgrowth was reduced by the siRNA against the INSR and the results of the CETSA suggested that the INSR showed a significant thermal stability-shifted effect upon AMA treatment. Other neurotrophic signaling pathways in PC12 cells were investigated using specific inhibitors, Western blotting and PC12(rasN17) and PC12(mtGAP) mutants. The inhibitors of the glucocorticoid receptor (GR), phospholipase C (PLC) and protein kinase C (PKC), Ras, Raf and mitogen-activated protein kinase (MEK) significantly reduced the neurite outgrowth induced by AMA in PC12 cells. Furthermore, the phosphorylation reactions of GR, PLC, PKC and an extracellular signal-regulated kinase (ERK) were significantly increased after inducing AMA and markedly decreased after treatment with the corresponding inhibitors. Collectively, these results suggested that AMA-induced neuritogenic activity in PC12 cells potentially depended on targeting the INSR and activating the downstream Ras/Raf/ERK and PI3K/AKT signaling pathways. In addition, the GR/PLC/PKC signaling pathway was found to be involved in the neurogenesis effect of AMA.


2003 ◽  
Vol 163 (5) ◽  
pp. 1067-1076 ◽  
Author(s):  
Mitsunobu Hoshino ◽  
Shun Nakamura

The novel Ras-like small GTPase Rin is expressed prominently in adult neurons, and binds calmodulin (CaM) through its COOH-terminal–binding motif. It might be involved in calcium/CaM-mediated neuronal signaling, but Rin-mediated signal transduction pathways have not yet been elucidated. Here, we show that expression of Rin induces neurite outgrowth without nerve growth factor or mitogen-activated protein kinase activation in rat pheochromocytoma PC12 cells. Rin-induced neurite outgrowth was markedly inhibited by coexpression with dominant negative Rac/Cdc42 protein or CaM inhibitor treatment. We also found that expression of Rin elevated the endogenous Rac/Cdc42 activity. Rin mutant proteins, in which the mutation disrupted association with CaM, failed to induce neurite outgrowth irrespective of Rac/Cdc42 activation. Disruption of endogenous Rin function inhibited the neurite outgrowth stimulated by forskolin and extracellular calcium entry through voltage-dependent calcium channel evoked by KCl. These findings suggest that Rin-mediated neurite outgrowth signaling requires not only endogenous Rac/Cdc42 activation but also Rin–CaM association, and that endogenous Rin is involved in calcium/CaM-mediated neuronal signaling pathways.


2014 ◽  
Vol 39 (1) ◽  
pp. 104-112 ◽  
Author(s):  
Kursat Oguz Yaykasli ◽  
Omer Faruk Hatipoglu ◽  
Emine Yaykasli ◽  
Kubra Yildirim ◽  
Ertugrul Kaya ◽  
...  

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