Abstract
Background: Eph receptors play important functions in developmental processes and diseases and among them EphA2 is well known for its controversial role in cancer. Drug discovery strategies are mainly centered on EphA2 extracellular ligand-binding domain however, the receptor also contains a largely unexplored cytosolic Sam (Sterile alpha motif) domain at the C-terminus. EphA2-Sam binds the Sam domain from the lipid phosphatase Ship2 and the first Sam domain of Odin. Sam-Sam interactions may be important to regulate ligand-induced receptor endocytosis and degradation i.e., processes that could be engaged against tumor malignancy.
Methods: We critically analyzed literature related to a) Eph receptors with particular emphasis on EphA2 and its role in cancer, b) Sam domains, c) heterotypic Sam-Sam interactions involving EphA2-Sam.
Results: While literature data indicate that binding of EphA2-Sam to Ship2-Sam should largely generate pro-oncogenic effects in cancer cells, the correlation between EphA2- Sam/Odin-Sam1 complex and the disease is unclear. Recently a few linear peptides encompassing binding interfaces from either Ship2-Sam and Odin-Sam1 have been characterized but failed to efficiently block heterotypic Sam-Sam interactions involving EphA2-Sam due to the lack of a native like fold.
Conclusion: Molecule antagonists of heterotypic EphA2-Sam associations could work as potential anticancer agents or be implemented as tools to further clarify receptor functions and eventually validate its role as a novel target in the field of anti-cancer drug discovery. Due to the failure of linear peptides there is a crucial need for novel approaches, based on cyclic or helical molecules, to target Sam-Sam interfaces.
Keywords: Receptor tyrosine kinase, EphA2, Sam domain, protein-protein interactions, cancer, novel target.
Current Medicinal Chemistry
Title:The Sam Domain of EphA2 Receptor and its Relevance to Cancer: A Novel Challenge for Drug Discovery?
Volume: 23 Issue: 42
Author(s): Flavia A. Mercurio and Marilisa Leone
Affiliation:
Keywords: Receptor tyrosine kinase, EphA2, Sam domain, protein-protein interactions, cancer, novel target.
Abstract: Background: Eph receptors play important functions in developmental processes and diseases and among them EphA2 is well known for its controversial role in cancer. Drug discovery strategies are mainly centered on EphA2 extracellular ligand-binding domain however, the receptor also contains a largely unexplored cytosolic Sam (Sterile alpha motif) domain at the C-terminus. EphA2-Sam binds the Sam domain from the lipid phosphatase Ship2 and the first Sam domain of Odin. Sam-Sam interactions may be important to regulate ligand-induced receptor endocytosis and degradation i.e., processes that could be engaged against tumor malignancy.
Methods: We critically analyzed literature related to a) Eph receptors with particular emphasis on EphA2 and its role in cancer, b) Sam domains, c) heterotypic Sam-Sam interactions involving EphA2-Sam.
Results: While literature data indicate that binding of EphA2-Sam to Ship2-Sam should largely generate pro-oncogenic effects in cancer cells, the correlation between EphA2- Sam/Odin-Sam1 complex and the disease is unclear. Recently a few linear peptides encompassing binding interfaces from either Ship2-Sam and Odin-Sam1 have been characterized but failed to efficiently block heterotypic Sam-Sam interactions involving EphA2-Sam due to the lack of a native like fold.
Conclusion: Molecule antagonists of heterotypic EphA2-Sam associations could work as potential anticancer agents or be implemented as tools to further clarify receptor functions and eventually validate its role as a novel target in the field of anti-cancer drug discovery. Due to the failure of linear peptides there is a crucial need for novel approaches, based on cyclic or helical molecules, to target Sam-Sam interfaces.
Export Options
About this article
Cite this article as:
Mercurio A. Flavia and Leone Marilisa, The Sam Domain of EphA2 Receptor and its Relevance to Cancer: A Novel Challenge for Drug Discovery?, Current Medicinal Chemistry 2016; 23 (42) . https://dx.doi.org/10.2174/0929867323666161101100722
DOI https://dx.doi.org/10.2174/0929867323666161101100722 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Synthetic Lethality to Overcome Cancer Drug Resistance
Current Medicinal Chemistry Tacrine Derivatives and Alzheimers Disease
Current Medicinal Chemistry Adult Stem Cells and Biocompatible Scaffolds as Smart Drug Delivery Tools for Cardiac Tissue Repair
Current Medicinal Chemistry Neurokinin-1 Receptor Antagonists in Lung Cancer Therapy
Letters in Drug Design & Discovery The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development
Current Molecular Medicine Scientific Basis for the Use of Indian Ayurvedic Medicinal Plants in the Treatment of Neurodegenerative Disorders: 1. Ashwagandha
Central Nervous System Agents in Medicinal Chemistry Peptide-Receptor Ligands and Multivalent Approach
Anti-Cancer Agents in Medicinal Chemistry Natural Products Targeting Cancer Stem Cells: A Revisit
Current Medicinal Chemistry Real Time Analysis of Neurotransmitters in the Brain Using a Micro-Electrode System
Current Neurovascular Research Design and Microwave-Assisted Synthesis of Aza-Resveratrol Analogs with Potent Cholinesterase Inhibition
CNS & Neurological Disorders - Drug Targets SiRNA Mediated Gene Silencing: Hurdles, Strategies and Applications
Pharmaceutical Nanotechnology Metastasis-Inducing S100A4 Protein: Implication in Non-Malignant Human Pathologies
Current Molecular Medicine Dynamic Medicinal Chemistry in the Elaboration of Morphine-6- Glucuronide Analogs
Current Topics in Medicinal Chemistry Interaction of Endocannabinoid Receptors with Biological Membranes
Current Medicinal Chemistry Antineoplastic Potential of Medicinal Plants
Recent Patents on Biotechnology (Neuro)Transmitter Systems in Circulating Immune Cells: A Target of Immunopharmacological Interventions?
Current Medicinal Chemistry Anti-Cancer/Anti-Tumor
Current Bioactive Compounds Targeting Schistosome Histone Modifying Enzymes for Drug Development
Current Pharmaceutical Design Association of Oxidative Stress to the Genesis of Anxiety: Implications for Possible Therapeutic Interventions
Current Neuropharmacology Dual-Specificity MAP Kinase Phosphatases as Targets of Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry