scholarly journals HPD degradation regulated by the TTC36-STK33-PELI1 signaling axis induces tyrosinemia and neurological damage

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yajun Xie ◽  
Xiaoyan Lv ◽  
Dongsheng Ni ◽  
Jianing Liu ◽  
Yanxia Hu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Learning And Memory ◽  
Molecular Chaperone ◽  
Neurological Disorders ◽  
Hippocampal Neurons ◽  
Neurological Damage ◽  
Fha Domain ◽  
Signaling Axis ◽  
Tyrosine Metabolism ◽  
Key Enzyme

Abstract Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. Conversely, deficiency or depletion of TTC36 results in enhanced STK33-mediated HPD T382 phosphorylation and binding of PELI1 to HPD and subsequent PELI1-mediated HPD downregulation. Ttc36−/− mice have reduced HPD expression in the liver and exhibit tyrosinemia, damage to hippocampal neurons, and deficits of learning and memory. These findings reveal a previously unknown regulation of HPD expression and highlight the physiological significance of TTC36-STK33-PELI1-regulated HPD expression in tyrosinemia and tyrosinemia-associated neurological disorders.

scholarly journals The p38MAPK-MK2 Signaling Axis as a Critical Link Between Inflammation and Synaptic Transmission

2021 ◽  
Vol 9 ◽  
Author(s):  
Edward Beamer ◽  
Sonia A. L. Corrêa
Keyword(s):  
Synaptic Plasticity ◽  
Protein Kinase ◽  
Neurological Disorders ◽  
Metabotropic Glutamate Receptors ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Group I ◽  
Signaling Axis

p38 is a mitogen-activated protein kinase (MAPK), that responds primarily to stress stimuli. p38 has a number of targets for phosphorylation, including MAPK-activated protein kinase 2 (MK2). MK2 primarily functions as a master regulator of RNA-binding proteins, indirectly controlling gene expression at the level of translation. The role of MK2 in regulating the synthesis of pro-inflammatory cytokines downstream of inflammation and cellular stress is well-described. A significant amount of evidence, however, now points to a role for the p38MAPK-MK2 signaling axis in mediating synaptic plasticity through control of AMPA receptor trafficking and the morphology of dendritic spines. These processes are mediated through control of cytoskeletal dynamics via the activation of cofilin-1 and possibly control of the expression of Arc/Arg3.1. There is evidence that MK2 is necessary for group I metabotropic glutamate receptors long-term depression (mGluR-LTD). Disruption of this signaling may play an important role in mediating cognitive dysfunction in neurological disorders such as fragile X syndrome and Alzheimer’s disease. To date, the role of neuronal MK2 mediating synaptic plasticity in response to inflammatory stimuli has not yet been investigated. In immune cells, it is clear that MK2 is phosphorylated following activation of a broad range of cell surface receptors for cytokines and other inflammatory mediators. We propose that neuronal MK2 may be an important player in the link between inflammatory states and dysregulation of synaptic plasticity underlying cognitive functions. Finally, we discuss the potential of the p38MAPK-MK2 signaling axis as target for therapeutic intervention in a number of neurological disorders.

scholarly journals The amounts of rat liver cyclic AMP-dependent protein kinase I and II are differentially regulated by diet

1988 ◽  
Vol 256 (2) ◽  
pp. 447-452 ◽  
Author(s):  
R Ekanger ◽  
O K Vintermyr ◽  
S O Døskeland
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Protein Restriction ◽  
Type I ◽  
Short Term ◽  
Rat Hepatocyte ◽  
Dependent Protein Kinase ◽  
Key Enzyme ◽  
Dependent Protein ◽  
Fasted Rats

1. The fluctuations in rat hepatocyte volume and protein content in response to dietary perturbations (starvation, protein restriction, refeeding) were accompanied by corresponding fluctuations in the amount of the regulatory (R) and catalytic (C) subunits of cyclic AMP-dependent protein kinase. Thus the intracellular concentration of this key enzyme was adjusted to be near constant. 2. The adjustment of cellular R was accomplished almost exclusively by regulating cytosolic RI (R subunit of type I kinase). The preferential down-regulation of cytosolic RI in response to starvation/protein restriction indicates that particulate RI and cytosolic as well as particulate RII are more resistant to breakdown during general catabolism in the hepatocyte. 3. The diet-induced fluctuations of kinase subunits were uniformly distributed in all populations of parenchymatous hepatocytes, regardless of their size and density. It is thus possible to isolate hepatocytes with uniformly altered RI/RII ratio from livers of rats with different feeding regimens. 4. The binding of endogenous cyclic AMP to RI and RII was similar in livers with high RI/RII ratio (fed rats) and low RI/RII ratio (fasted rats) as well as in hepatocytes isolated from fasted rats. Under the conditions of the experiment (short-term stimulation by glucagon), therefore, neither the dietary state nor the RI/RII ratio seemed to affect the apparent affinity of the isoreceptors for cyclic AMP. However, RI appeared to show a slightly higher co-operativity of intracellular cyclic AMP binding than did RII in all states.

scholarly journals The Effects of Propofol on Hypoxia- and TNF-α-Mediated Brain-Derived Neurotrophic Factor/Tyrosine Kinase Receptor B Pathway Dysregulation in Primary Rat Hippocampal Neurons and Astrocytes

2021 ◽  
Author(s):  
Weiping Tao ◽  
Xuesong Zhang ◽  
Juan Ding ◽  
Shijian Yu ◽  
Peiqing Ge ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Neurotrophic Factor ◽  
Neurological Disorders ◽  
Hippocampal Neurons ◽  
Inhibitory Effect ◽  
Tyrosine Kinase Receptor ◽  
Protective Properties ◽  
Tnf Α ◽  
Underlying Mechanisms ◽  
Pathway Dysregulation

Abstract Background: BDNF/TrkB pathway dysregulation may be induced by hypoxia and inflammation, and play pivotal roles during the development of neurological disorders. Propofol is an anesthetic agent with neuro-protective properties. We aimed to verify whether propofol affected BDNF/TrkB pathway in neurons exposed to hypoxia or TNF-α.Methods: Primary rat hippocampal neurons and astrocytes were cultured and exposed to propofol followed by hypoxia or TNF-α treatment. The production of BDNF and the expression/truncation/phosphorylation of TrkB were measured. The underlying mechanisms such as ERK, CREB, p35 and Cdk5 were investigated.Results: In hippocampal neurons and astrocytes, hypoxia and TNF-α reduced the production of BDNF. Pretreatment of hippocampal neurons with 25μM propofol reversed the inhibitory effect of hypoxia or TNF-α on BDNF production. However, even 100μM propofol had no such effect in astrocytes. Further, we found that in hippocampal neurons hypoxia and TNF-α increased the phosphorylaion of ERK (p-ERK) and CREB at Ser142 (p-CREBSer142), while reduced the phosphorylation of CREB at Ser133 (p-CREBSer133), which were all reversed by 25μM propofol and 10μM ERK inhibitor. In addition, neither hypoxia nor TNF-α affected TrkB expression, truncation or phosphorylation in hippocampal neurons and astrocytes. However 50μM propofol induced TrkB phosphorylation without affecting its expression and truncation only in hippocampal neurons. Furthermore, we detected that in hippocampal neurons, 50μM propofol induced p35 expression and Cdk5 activation, and blockade of p35 or Cdk5 mitigated propofol-induced TrkB phosphorylation.Conclusions: Propofol, via ERK/CREB and p35/Cdk5, may modulate BDNF/TrkB pathway in hippocampal neurons that were exposed to hypoxia or TNF-α.

scholarly journals Protein kinase C phosphorylation of rat liver S-adenosylmethionine synthetase: dissociation and production of an active monomer

1994 ◽  
Vol 303 (3) ◽  
pp. 949-955 ◽  
Author(s):  
M A Pajares ◽  
C Durán ◽  
F Corrales ◽  
J M Mato
Keyword(s):  
Alkaline Phosphatase ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Rat Liver ◽  
Oligomeric State ◽  
Kinase C ◽  
Phosphatase Treatment ◽  
Key Enzyme ◽  
Adenosylmethionine Synthetase ◽  
Adomet Synthetase

The regulation of rat liver S-adenosylmethionine synthetase (AdoMet synthetase), a key enzyme in methionine metabolism, by protein kinase C (PKC) phosphorylation has been studied. Both enzyme forms, tetramer and dimer, are phosphorylated by this kinase in the same residue, Thr-342, of the sequence. Phosphorylation of the dimer leads to its dissociation, with production of a fully-active monomer. The kinetics of the monomer have been studied, and a KmMet of 931.9 microM, a KmATP of 708 microM and a Vmax of 66.8 nmol/min/mg have been calculated. Alkaline phosphatase treatment of both enzyme forms (tetramer and dimer) produces a reduction in their activity with no change in the oligomeric state. On the other hand, PKC phosphorylation of the alkaline phosphatase-treated AdoMet synthetase forms leads to the dissociation of the dimer to produce a monomer. Rephosphorylation occurs again in the same residue, Thr-342, of the sequence. The significance of AdoMet synthetase regulation by PKC phosphorylation is further discussed.

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