Abstract
It is well established that the immunosuppressive effects of cyclosporin A (CsA) and FK506 (also known as tacrolimus) are mediated through binding to their cognate cellular proteins cyclophilin and FKBP (collectively termed immunophilins), respectively. Biochemical analysis had revealed that cyclophilin-CsA and FKBP-FK506 complexes bind to and inactivate Ca2+- dependent serine / threonine phosphatase calcineurin. Since calcineurin regulates nuclear translocation and subsequent activation of nuclear factor of activated T cells (NFAT) transcription factors that is one of essential steps for cytokine gene expression in activated T cells, it is believed that inhibition of calcineurin is a molecular basis of the immunosuppressive properties of CsA and FK506. However, recent studies indicate that both CsA and FK506 can block activation of JNK and p38 signaling pathways during T cell activation. CsA and FK506, thus, have two distinct mechanisms of action; one is the inhibition of the protein phosphatase activity of calcineurin, leading to the blockade of the nuclear translocation of NFAT transcription factors, and the other is the suppression of JNK and p38 activation pathways. It is likely that the presence of two distinct targets in T cell activation makes CsA and FK506 highly potent immunosuppressive drugs. Here we discuss the action of immunophilin-ligand complexes on JNK and p38 activation pathways. We also argue the possibility of immunotherapeutic application targeting at JNK and p38 signaling pathways.
Keywords: mapk signaling pathways, immunophilin-ligand complex, immunosuppressive effects, cognate cellular proteins, fkbp-fk506 complexes, nuclear factor of activated T cells, immunosuppressive drugs, p38 signaling pathways
Current Topics in Medicinal Chemistry
Title: Regulation of MAPK Signaling Pathways Through Immunophilin-ligand Complex
Volume: 3 Issue: 12
Author(s): Satoshi Matsuda and Shigeo Koyasu
Affiliation:
Keywords: mapk signaling pathways, immunophilin-ligand complex, immunosuppressive effects, cognate cellular proteins, fkbp-fk506 complexes, nuclear factor of activated T cells, immunosuppressive drugs, p38 signaling pathways
Abstract: It is well established that the immunosuppressive effects of cyclosporin A (CsA) and FK506 (also known as tacrolimus) are mediated through binding to their cognate cellular proteins cyclophilin and FKBP (collectively termed immunophilins), respectively. Biochemical analysis had revealed that cyclophilin-CsA and FKBP-FK506 complexes bind to and inactivate Ca2+- dependent serine / threonine phosphatase calcineurin. Since calcineurin regulates nuclear translocation and subsequent activation of nuclear factor of activated T cells (NFAT) transcription factors that is one of essential steps for cytokine gene expression in activated T cells, it is believed that inhibition of calcineurin is a molecular basis of the immunosuppressive properties of CsA and FK506. However, recent studies indicate that both CsA and FK506 can block activation of JNK and p38 signaling pathways during T cell activation. CsA and FK506, thus, have two distinct mechanisms of action; one is the inhibition of the protein phosphatase activity of calcineurin, leading to the blockade of the nuclear translocation of NFAT transcription factors, and the other is the suppression of JNK and p38 activation pathways. It is likely that the presence of two distinct targets in T cell activation makes CsA and FK506 highly potent immunosuppressive drugs. Here we discuss the action of immunophilin-ligand complexes on JNK and p38 activation pathways. We also argue the possibility of immunotherapeutic application targeting at JNK and p38 signaling pathways.
Export Options
About this article
Cite this article as:
Matsuda Satoshi and Koyasu Shigeo, Regulation of MAPK Signaling Pathways Through Immunophilin-ligand Complex, Current Topics in Medicinal Chemistry 2003; 3 (12) . https://dx.doi.org/10.2174/1568026033451916
DOI https://dx.doi.org/10.2174/1568026033451916 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Surgical Management of Heart Failure
Current Cardiology Reviews Pharmacological Management of Diabetes for Reducing Glucose Levels and Cardiovascular Disease Risk: What Evidence in South Asians?
Current Diabetes Reviews Pleiotropic Effects of Simvastatin on Some Calcium Regulatory and Myofibrillar Proteins in Ischemic/Reperfused Heart: Causality of Statins Cardioprotection?
Current Pharmaceutical Design Effect of Ranolazine in Preventing Postoperative Atrial Fibrillation in Patients Undergoing Coronary Revascularization Surgery
Current Vascular Pharmacology Discovery and Development of Purine-Scaffold Hsp90 Inhibitors
Current Topics in Medicinal Chemistry Chaperonopathies and Chaperonotherapy. Hsp60 as Therapeutic Target in Cancer: Potential Benefits and Risks
Current Pharmaceutical Design Cardiac and Muscular Involvement in Idiopathic Inflammatory Myopathies: Noninvasive Diagnostic Assessment and the Role of Cardiovascular and Skeletal Magnetic Resonance Imaging
Inflammation & Allergy - Drug Targets (Discontinued) Recent Advances in Targeted Anti-Vasculature Therapy: The Neuroblastoma Model
Current Drug Targets A Practical Guide for the Treatment of Symptomatic Heart Failure with Reduced Ejection Fraction (HFrEF)
Current Cardiology Reviews Novel Strategies to Delineate Matrix Metalloproteinase (MMP)-Substrate Relationships and Identify Targets to Block MMP Activity
Mini-Reviews in Medicinal Chemistry Serum Creatinine vs. Albuminuria as Biomarkers for the Estimation of Cardiovascular Risk
Current Vascular Pharmacology Pharmacological Evaluation of Polar Extract of <i>Chrozophora</i> tinctoria for Effective Treatment of Cancer: <i>In Vitro</i> Qualitative and Quantitative Analysis
Current Nutraceuticals Midkine in Inflammatory and Toxic Conditions
Current Drug Delivery Ability of older people with dementia or cognitive impairment to manage medicine regimens: a narrative review
Current Clinical Pharmacology The Involvement of Lysosomes in Myocardial Aging and Disease
Current Cardiology Reviews Update on COX-2 Selective Inhibitors: Chemical Classification, Side Effects and their Use in Cancers and Neuronal Diseases
Current Topics in Medicinal Chemistry Relationship Between Na<sup>+</sup>, K<sup>+</sup>-ATPase and NMDA Receptor at Central Synapses
Current Protein & Peptide Science Trends in Mitochondrial Therapeutics for Neurological Disease
Current Medicinal Chemistry Antiangiogenic Therapy and Ovarian Cancer
Current Women`s Health Reviews Metabolic Targets of Cardiac HormonesTherapeutic Anti-Cancer Effects
Current Pharmaceutical Design