Serine/threonine phosphorylation regulates HNF-4α-dependent redox-mediated iNOS expression in hepatocytes

2003 ◽  
Vol 284 (4) ◽  
pp. C1090-C1099 ◽  
Author(s):  
Hongtao Guo ◽  
Junping Wei ◽  
Yusuke Inoue ◽  
Frank J. Gonzalez ◽  
Paul C. Kuo
Keyword(s):  
Oxidative Stress ◽  
Inos Expression ◽  
Hepatocyte Nuclear Factor ◽  
Promoter Activation ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Phosphorylation Pattern ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Kinase Signaling Pathway ◽  
Kinase Pathway

Nitric oxide (NO), endogenously synthesized by inducible NO synthase (iNOS), serves antioxidant and antiapoptotic functions in settings characterized by oxidative stress and proinflammatory cytokines such as sepsis and shock. However, the redox-sensitive mechanisms regulating hepatocyte expression of iNOS are largely unknown. In interleukin-1β (IL-1β)-stimulated hepatocytes exposed to superoxide, we demonstrate that hepatocyte nuclear factor-4α (HNF-4α) acts as an activator of redox-associated hepatocyte iNOS expression at the level of protein, mRNA, and promoter activation. In the absence of HNF-4α, this redox-mediated enhancement is ablated. HNF-4α functional activity is associated with a unique serine/threonine kinase-mediated phosphorylation pattern. This suggests that a redox-sensitive kinase pathway targets HNF-4α to augment hepatocyte iNOS expression. Previous studies have not addressed a redox-dependent kinase signaling pathway that targets HNF-4α and enhances hepatocyte iNOS gene transcription. A unique pattern of phosphorylation determines HNF-4α activity as a trans-activator of IL-1β-mediated hepatocyte iNOS expression in the presence of oxidative stress.

scholarly journals WNK4 Kinase: from structure to physiology

2021 ◽  
Author(s):  
Adrian Rafael Murillo-de-Ozores ◽  
Alejandro Rodriguez-Gama ◽  
Hector Carbajal-Contreras ◽  
Gerardo Gamba ◽  
Maria Castaneda-Bueno
Keyword(s):  
Oxidative Stress ◽  
Mouse Models ◽  
Serine Threonine Kinase ◽  
Gene Encoding ◽  
Threonine Kinase ◽  
Physiological Conditions ◽  
Different Levels ◽  
Familial Hyperkalemic Hypertension

With No Lysine (K) kinase 4 (WNK4) belongs to a serine-threonine kinase family characterized by the atypical positioning of its catalytic lysine. Despite the fact that WNK4 has been found in many tissues, the majority of its study has revolved around its function in the kidney, specifically as a positive regulator of the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) of the nephron. This is explained by the description of gain-of-function mutations in the gene encoding WNK4 that cause Familial Hyperkalemic Hypertension (FHHt). This disease is mainly driven by increased downstream activation of the Ste20-related Proline Alanine Rich Kinase (SPAK)/Oxidative Stress Responsive Kinase 1 (OSR1)-NCC pathway, which increases salt reabsorption in the DCT and indirectly impairs renal K+ secretion. Here, we review the large volume of information that has accumulated about different aspects of WNK4 function. We first review the knowledge on WNK4 structure and enumerate the functional domains and motifs that have been characterized. Then, we discuss WNK4 physiological functions based on the information obtained from in vitro studies and from a diverse set of genetically modified mouse models with altered WNK4 function. We then review in vitro and in vivo evidence on the different levels of regulation of WNK4. Finally, we go through the evidence that has suggested how different physiological conditions act through WNK4 to modulate NCC activity.

Mammalian Sterile20-like kinase 1 and the regulation of apoptosis

2004 ◽  
Vol 32 (3) ◽  
pp. 485-488 ◽  
Author(s):  
P.M. de Souza ◽  
M.A. Lindsay
Keyword(s):  
Protein Kinase ◽  
Physiological Function ◽  
Mitogen Activated Protein Kinase ◽  
Serine Threonine Kinase ◽  
Mapk Kinase ◽  
Threonine Kinase ◽  
Abundant Evidence ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

Mammalian Sterile20-like kinase 1 (Mst1) is a ubiquitously expressed serine/threonine kinase which represents a member of the rapidly expanding family of enzymes related to the yeast Sterile20 kinase. Although the physiological function of Mst1 and its role in intracellular signalling is still unclear, reports to date suggest that Mst1, similar to its yeast homologue, operates in the MAPK (mitogen-activated protein kinase) pathway and, in this capacity, may represent a putative MAPK kinase kinase kinase. Moreover, there is abundant evidence for a role of this enzyme in apoptosis, where not only is it a target for caspases, but may also serve as an activator of these proteases to amplify the apoptotic signalling pathway. This paper reviews the investigations that have led to our current understanding of the mechanisms by which Mst1 may be activated and thereby contribute to apoptosis.

scholarly journals Fist/Hipk3

2000 ◽  
Vol 192 (8) ◽  
pp. 1165-1174 ◽  
Author(s):  
Véronique Rochat-Steiner ◽  
Karin Becker ◽  
Olivier Micheau ◽  
Pascal Schneider ◽  
Kim Burns ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Death Receptor ◽  
Death Domain ◽  
Serine Threonine Kinase ◽  
Interacting Protein ◽  
Threonine Kinase ◽  
Conserved Sequence ◽  
Mammalian Tissues ◽  
A Cell ◽  
Kinase Pathway

Fas is a cell surface death receptor that signals apoptosis. Several proteins have been identified that bind to the cytoplasmic death domain of Fas. Fas-associated death domain (FADD), which couples Fas to procaspase-8, and Daxx, which couples Fas to the Jun NH2-terminal kinase pathway, bind independently to the Fas death domain. We have identified a 130-kD kinase designated Fas-interacting serine/threonine kinase/homeodomain-interacting protein kinase (FIST/HIPK3) as a novel Fas-interacting protein. Binding to Fas is mediated by a conserved sequence in the COOH terminus of the protein. FIST/HIPK3 is widely expressed in mammalian tissues and is localized both in the nucleus and in the cytoplasm. In transfected cell lines, FIST/HIPK3 causes FADD phosphorylation, thereby promoting FIST/HIPK3–FADD–Fas interaction. Although Fas ligand–induced activation of Jun NH2-terminal kinase is impaired by overexpressed active FIST/HIPK3, cell death is not affected. These results suggest that Fas-associated FIST/HIPK3 modulates one of the two major signaling pathways of Fas.

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