Receptor Tyrosine Kinases in Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (28 February 2019) | Viewed by 91058

Special Issue Editor


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Guest Editor
Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Kunigami, Okinawa 904-0495, Japan
Interests: cell surface receptors; transmembrane signaling; receptor tyrosine kinases; learning and memory; decision-making; animal behavior
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Special Issue Information

Dear Colleagues

Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. There are a number of mechanisms by which the tight regulation of TRK signaling can be abrogated, including enhanced production of ligands, overproduction of TRK proteins, mutations leading constitutive activation of TRK, deficiency of TRK downregulation, and activation of TRK through cross-talk with heterologous cell-surface receptors. Dysregulation of these processes directly links to disease in humans. Small molecule inhibitors are widely used that can target RTK functionality in disease. Antibodies that inhibit RTKs have also been developed, and are in current use or development in the clinic.

The aim of this Special Issues of Cells is to offer an Open Access collection of reviews on forefront research on RTKs that covers all the above aspects.

Prof. Dr. Ichiro Maruyama
Guest Editor

 

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Keywords

  • anti-tumor drug
  • cancer
  • developmental syndrome
  • domain
  • growth factor
  • kinome
  • mental disorder
  • monoclonal antibody
  • nanobody
  • phosphorylation
  • preformed dimer
  • receptor tyrosine kinase
  • signal transduction
  • small chemical inhibitor
  • transmembrane signaling
  • tumor

Published Papers (11 papers)

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Research

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16 pages, 9324 KiB  
Communication
Lysosomal Sequestration Impairs the Activity of the Preclinical FGFR Inhibitor PD173074
by Bernhard Englinger, Sebastian Kallus, Julia Senkiv, Anna Laemmerer, Patrick Moser, Lisa Gabler, Diana Groza, Christian R. Kowol, Petra Heffeter, Michael Grusch and Walter Berger
Cells 2018, 7(12), 259; https://doi.org/10.3390/cells7120259 - 08 Dec 2018
Cited by 8 | Viewed by 4403
Abstract
Knowledge of intracellular pharmacokinetics of anticancer agents is imperative for understanding drug efficacy as well as intrinsic and acquired cellular resistance mechanisms. However, the factors driving subcellular drug distribution are complex and poorly understood. Here, we describe for the first time the intrinsic [...] Read more.
Knowledge of intracellular pharmacokinetics of anticancer agents is imperative for understanding drug efficacy as well as intrinsic and acquired cellular resistance mechanisms. However, the factors driving subcellular drug distribution are complex and poorly understood. Here, we describe for the first time the intrinsic fluorescence properties of the fibroblast growth factor receptor inhibitor PD1703074 as well as utilization of this physicochemical feature to investigate intracellular accumulation and compartmentalization of this compound in human lung cancer cells. Cell-free PD173074 fluorescence, intracellular accumulation and distribution were investigated using analytical chemistry and molecular biology approaches. Analyses on a subcellular scale revealed selective drug accumulation in lysosomes. Coincubation with inhibitors of lysosomal acidification strongly enhanced PD173074-mediated fibroblast growth factor receptor (FGFR) inhibition and cytotoxicity. In conclusion, intrinsic fluorescence enables analysis of molecular factors influencing intracellular pharmacokinetics of PD173074. Lysosome-alkalinizing agents might represent candidates for rational combination treatment, preventing cancer cell-intrinsic PD173074 resistance based on lysosomal trapping. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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Review

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19 pages, 1522 KiB  
Review
Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling
by Ana Raquel-Cunha, Diana Cardoso-Carneiro, Rui M. Reis and Olga Martinho
Cells 2019, 8(5), 442; https://doi.org/10.3390/cells8050442 - 10 May 2019
Cited by 24 | Viewed by 5292
Abstract
Lung cancer is the most deadly neoplasm with the highest incidence in both genders, with non-small cell lung cancer (NSCLC) being the most frequent subtype. Somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are key drivers [...] Read more.
Lung cancer is the most deadly neoplasm with the highest incidence in both genders, with non-small cell lung cancer (NSCLC) being the most frequent subtype. Somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are key drivers of NSCLC progression, with EGFR inhibitors being particularly beneficial for patients carrying the so-called “EGFR-sensitizing mutations”. However, patients eventually acquire resistance to these EGFR inhibitors, and a better knowledge of other driven and targetable proteins will allow the design of increasingly accurate drugs against patients’ specific molecular aberrations. Raf kinase inhibitory protein (RKIP) is an important modulator of relevant intracellular signaling pathways, including those controlled by EGFR, such as MAPK. It has been reported that it has metastasis suppressor activity and a prognostic role in several solid tumors, including lung cancer. In the present review, the potential use of RKIP in the clinic as a prognostic biomarker and predictor of therapy response in lung cancer is addressed. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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33 pages, 3378 KiB  
Review
Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer
by Marisa L. Martin-Fernandez, David T. Clarke, Selene K. Roberts, Laura C. Zanetti-Domingues and Francesco L. Gervasio
Cells 2019, 8(4), 316; https://doi.org/10.3390/cells8040316 - 05 Apr 2019
Cited by 35 | Viewed by 9992
Abstract
The epidermal growth factor receptor (EGFR) is historically the prototypical receptor tyrosine kinase, being the first cloned and the first where the importance of ligand-induced dimer activation was ascertained. However, many years of structure determination has shown that EGFR is not completely understood. [...] Read more.
The epidermal growth factor receptor (EGFR) is historically the prototypical receptor tyrosine kinase, being the first cloned and the first where the importance of ligand-induced dimer activation was ascertained. However, many years of structure determination has shown that EGFR is not completely understood. One challenge is that the many structure fragments stored at the PDB only provide a partial view because full-length proteins are flexible entities and dynamics play a key role in their functionality. Another challenge is the shortage of high-resolution data on functionally important higher-order complexes. Still, the interest in the structure/function relationships of EGFR remains unabated because of the crucial role played by oncogenic EGFR mutants in driving non-small cell lung cancer (NSCLC). Despite targeted therapies against EGFR setting a milestone in the treatment of this disease, ubiquitous drug resistance inevitably emerges after one year or so of treatment. The magnitude of the challenge has inspired novel strategies. Among these, the combination of multi-disciplinary experiments and molecular dynamic (MD) simulations have been pivotal in revealing the basic nature of EGFR monomers, dimers and multimers, and the structure-function relationships that underpin the mechanisms by which EGFR dysregulation contributes to the onset of NSCLC and resistance to treatment. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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19 pages, 1050 KiB  
Review
Modulation of Receptor Tyrosine Kinase Activity through Alternative Splicing of Ligands and Receptors in the VEGF-A/VEGFR Axis
by Megan Stevens and Sebastian Oltean
Cells 2019, 8(4), 288; https://doi.org/10.3390/cells8040288 - 28 Mar 2019
Cited by 34 | Viewed by 5514
Abstract
Vascular endothelial growth factor A (VEGF-A) signaling is essential for physiological and pathological angiogenesis. Alternative splicing of the VEGF-A pre-mRNA gives rise to a pro-angiogenic family of isoforms with a differing number of amino acids (VEGF-Axxxa), as well as a family [...] Read more.
Vascular endothelial growth factor A (VEGF-A) signaling is essential for physiological and pathological angiogenesis. Alternative splicing of the VEGF-A pre-mRNA gives rise to a pro-angiogenic family of isoforms with a differing number of amino acids (VEGF-Axxxa), as well as a family of isoforms with anti-angiogenic properties (VEGF-Axxxb). The biological functions of VEGF-A proteins are mediated by a family of cognate protein tyrosine kinase receptors, known as the VEGF receptors (VEGFRs). VEGF-A binds to both VEGFR-1, largely suggested to function as a decoy receptor, and VEGFR-2, the predominant signaling receptor. Both VEGFR-1 and VEGFR-2 can also be alternatively spliced to generate soluble isoforms (sVEGFR-1/sVEGFR-2). The disruption of the splicing of just one of these genes can result in changes to the entire VEGF-A/VEGFR signaling axis, such as the increase in VEGF-A165a relative to VEGF-A165b resulting in increased VEGFR-2 signaling and aberrant angiogenesis in cancer. Research into this signaling axis has recently focused on manipulating the splicing of these genes as a potential therapeutic avenue in disease. Therefore, further research into understanding the mechanisms by which the splicing of VEGF-A/VEGFR-1/VEGFR-2 is regulated will help in the development of drugs aimed at manipulating splicing or inhibiting specific splice isoforms in a therapeutic manner. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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17 pages, 887 KiB  
Review
C-Met as a Key Factor Responsible for Sustaining Undifferentiated Phenotype and Therapy Resistance in Renal Carcinomas
by Paulina Marona, Judyta Górka, Jerzy Kotlinowski, Marcin Majka, Jolanta Jura and Katarzyna Miekus
Cells 2019, 8(3), 272; https://doi.org/10.3390/cells8030272 - 22 Mar 2019
Cited by 22 | Viewed by 4240
Abstract
C-Met tyrosine kinase receptor plays an important role under normal and pathological conditions. In tumor cells’ overexpression or incorrect activation of c-Met, this leads to stimulation of proliferation, survival and increase of motile activity. This receptor is also described as a marker of [...] Read more.
C-Met tyrosine kinase receptor plays an important role under normal and pathological conditions. In tumor cells’ overexpression or incorrect activation of c-Met, this leads to stimulation of proliferation, survival and increase of motile activity. This receptor is also described as a marker of cancer initiating cells. The latest research shows that the c-Met receptor has an influence on the development of resistance to targeted cancer treatment. High c-Met expression and activation in renal cell carcinomas is associated with the progression of the disease and poor survival of patients. C-Met receptor has become a therapeutic target in kidney cancer. However, the therapies used so far using c-Met tyrosine kinase inhibitors demonstrate resistance to treatment. On the other hand, the c-Met pathway may act as an alternative target pathway in tumors that are resistant to other therapies. Combination treatment together with c-Met inhibitor reduces tumor growth, vascularization and pro-metastatic behavior and results in suppressed mesenchymal phenotype and vascular endothelial growth factor (VEGF) secretion. Recently, it has been shown that the acquirement of mesenchymal phenotype or lack of cell differentiation might be related to the presence of the c-Met receptor and is consequently responsible for therapy resistance. This review presents the results from recent studies identifying c-Met as an important factor in renal carcinomas being responsible for tumor growth, progression and metastasis, indicating the role of c-Met in resistance to antitumor therapy and demonstrating the pivotal role of c-Met in supporting mesenchymal cell phenotype. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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20 pages, 2550 KiB  
Review
Two Birds, One Stone: Double Hits on Tumor Growth and Lymphangiogenesis by Targeting Vascular Endothelial Growth Factor Receptor 3
by Ming-Chuan Hsu, Mei-Ren Pan and Wen-Chun Hung
Cells 2019, 8(3), 270; https://doi.org/10.3390/cells8030270 - 21 Mar 2019
Cited by 42 | Viewed by 9767
Abstract
Vascular endothelial growth factor receptor 3 (VEGFR3) has been known for its involvement in tumor-associated lymphangiogenesis and lymphatic metastasis. The VEGFR3 signaling is stimulated by its main cognate ligand, vascular endothelial growth factor C (VEGF-C), which in turn promotes tumor progression. Activation of [...] Read more.
Vascular endothelial growth factor receptor 3 (VEGFR3) has been known for its involvement in tumor-associated lymphangiogenesis and lymphatic metastasis. The VEGFR3 signaling is stimulated by its main cognate ligand, vascular endothelial growth factor C (VEGF-C), which in turn promotes tumor progression. Activation of VEGF-C/VEGFR3 signaling in lymphatic endothelial cells (LECs) was shown to enhance the proliferation of LECs and the formation of lymphatic vessels, leading to increased lymphatic metastasis of tumor cells. In the past decade, the expression and pathological roles of VEGFR3 in tumor cells have been described. Moreover, the VEGF-C/VEGFR3 axis has been implicated in regulating immune tolerance and suppression. Therefore, the inhibition of the VEGF-C/VEGFR3 axis has emerged as an important therapeutic strategy for the treatment of cancer. In this review, we discuss the current findings related to VEGF-C/VEGFR3 signaling in cancer progression and recent advances in the development of therapeutic drugs targeting VEGF-C/VEGFR3. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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19 pages, 1307 KiB  
Review
The Dual Role of TAM Receptors in Autoimmune Diseases and Cancer: An Overview
by Martha Wium, Juliano D. Paccez and Luiz F. Zerbini
Cells 2018, 7(10), 166; https://doi.org/10.3390/cells7100166 - 12 Oct 2018
Cited by 44 | Viewed by 7833
Abstract
Receptor tyrosine kinases (RTKs) regulate cellular processes by converting signals from the extracellular environment to the cytoplasm and nucleus. Tyro3, Axl, and Mer (TAM) receptors form an RTK family that plays an intricate role in tissue maintenance, phagocytosis, and inflammation as well as [...] Read more.
Receptor tyrosine kinases (RTKs) regulate cellular processes by converting signals from the extracellular environment to the cytoplasm and nucleus. Tyro3, Axl, and Mer (TAM) receptors form an RTK family that plays an intricate role in tissue maintenance, phagocytosis, and inflammation as well as cell proliferation, survival, migration, and development. Defects in TAM signaling are associated with numerous autoimmune diseases and different types of cancers. Here, we review the structure of TAM receptors, their ligands, and their biological functions. We discuss the role of TAM receptors and soluble circulating TAM receptors in the autoimmune diseases systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Lastly, we discuss the effect of TAM receptor deregulation in cancer and explore the therapeutic potential of TAM receptors in the treatment of diseases. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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14 pages, 808 KiB  
Review
Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer
by Navid Sobhani, Anna Ianza, Alberto D’Angelo, Giandomenico Roviello, Fabiola Giudici, Marina Bortul, Fabrizio Zanconati, Cristina Bottin and Daniele Generali
Cells 2018, 7(7), 76; https://doi.org/10.3390/cells7070076 - 15 Jul 2018
Cited by 32 | Viewed by 7069
Abstract
Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is [...] Read more.
Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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24 pages, 2418 KiB  
Review
Receptor Tyrosine Kinase Ubiquitination and De-Ubiquitination in Signal Transduction and Receptor Trafficking
by William R. Critchley, Caroline Pellet-Many, Benjamin Ringham-Terry, Michael A. Harrison, Ian C. Zachary and Sreenivasan Ponnambalam
Cells 2018, 7(3), 22; https://doi.org/10.3390/cells7030022 - 15 Mar 2018
Cited by 39 | Viewed by 10836
Abstract
Receptor tyrosine kinases (RTKs) are membrane-based sensors that enable rapid communication between cells and their environment. Evidence is now emerging that interdependent regulatory mechanisms, such as membrane trafficking, ubiquitination, proteolysis and gene expression, have substantial effects on RTK signal transduction and cellular responses. [...] Read more.
Receptor tyrosine kinases (RTKs) are membrane-based sensors that enable rapid communication between cells and their environment. Evidence is now emerging that interdependent regulatory mechanisms, such as membrane trafficking, ubiquitination, proteolysis and gene expression, have substantial effects on RTK signal transduction and cellular responses. Different RTKs exhibit both basal and ligand-stimulated ubiquitination, linked to trafficking through different intracellular compartments including the secretory pathway, plasma membrane, endosomes and lysosomes. The ubiquitin ligase superfamily comprising the E1, E2 and E3 enzymes are increasingly implicated in this post-translational modification by adding mono- and polyubiquitin tags to RTKs. Conversely, removal of these ubiquitin tags by proteases called de-ubiquitinases (DUBs) enables RTK recycling for another round of ligand sensing and signal transduction. The endocytosis of basal and activated RTKs from the plasma membrane is closely linked to controlled proteolysis after trafficking and delivery to late endosomes and lysosomes. Proteolytic RTK fragments can also have the capacity to move to compartments such as the nucleus and regulate gene expression. Such mechanistic diversity now provides new opportunities for modulating RTK-regulated cellular responses in health and disease states. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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9 pages, 472 KiB  
Review
Targeting FLT3 Mutations in Acute Myeloid Leukemia
by Riad El Fakih, Walid Rasheed, Yousef Hawsawi, Maamoun Alsermani and Mona Hassanein
Cells 2018, 7(1), 4; https://doi.org/10.3390/cells7010004 - 08 Jan 2018
Cited by 29 | Viewed by 9248
Abstract
The FMS-like tyrosine kinase 3 (FLT3) pathway has an important role in cellular proliferation, survival, and differentiation. Acute myeloid leukemia (AML) patients with mutated FLT3 have a large disease burden at presentation and a dismal prognosis. A number of FLT3 inhibitors have been [...] Read more.
The FMS-like tyrosine kinase 3 (FLT3) pathway has an important role in cellular proliferation, survival, and differentiation. Acute myeloid leukemia (AML) patients with mutated FLT3 have a large disease burden at presentation and a dismal prognosis. A number of FLT3 inhibitors have been developed over the years. The first-generation inhibitors are largely non-specific, while the second-generation inhibitors are more specific and more potent. These inhibitors are used to treat patients with FLT3-mutated AML in virtually all disease settings including induction, consolidation, maintenance, relapse, and after hematopoietic cell transplantation (HCT). In this article, we will review the use of FLT3 inhibitors in AML. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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1510 KiB  
Review
Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The “Rotation Model”
by Endang R. Purba, Ei-ichiro Saita and Ichiro N. Maruyama
Cells 2017, 6(2), 13; https://doi.org/10.3390/cells6020013 - 02 Jun 2017
Cited by 116 | Viewed by 15039
Abstract
The epidermal growth factor receptor (EGFR) plays vital roles in cellular processes including cell proliferation, survival, motility, and differentiation. The dysregulated activation of the receptor is often implicated in human cancers. EGFR is synthesized as a single-pass transmembrane protein, which consists of an [...] Read more.
The epidermal growth factor receptor (EGFR) plays vital roles in cellular processes including cell proliferation, survival, motility, and differentiation. The dysregulated activation of the receptor is often implicated in human cancers. EGFR is synthesized as a single-pass transmembrane protein, which consists of an extracellular ligand-binding domain and an intracellular kinase domain separated by a single transmembrane domain. The receptor is activated by a variety of polypeptide ligands such as epidermal growth factor and transforming growth factor α. It has long been thought that EGFR is activated by ligand-induced dimerization of the receptor monomer, which brings intracellular kinase domains into close proximity for trans-autophosphorylation. An increasing number of diverse studies, however, demonstrate that EGFR is present as a pre-formed, yet inactive, dimer prior to ligand binding. Furthermore, recent progress in structural studies has provided insight into conformational changes during the activation of a pre-formed EGFR dimer. Upon ligand binding to the extracellular domain of EGFR, its transmembrane domains rotate or twist parallel to the plane of the cell membrane, resulting in the reorientation of the intracellular kinase domain dimer from a symmetric inactive configuration to an asymmetric active form (the “rotation model”). This model is also able to explain how oncogenic mutations activate the receptor in the absence of the ligand, without assuming that the mutations induce receptor dimerization. In this review, we discuss the mechanisms underlying the ligand-induced activation of the preformed EGFR dimer, as well as how oncogenic mutations constitutively activate the receptor dimer, based on the rotation model. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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