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Cells
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New Insights into Tyrosine Kinase Alterations in Human Diseases
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New Insights into Tyrosine Kinase Alterations in Human Diseases

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

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 11537

Special Issue Editors

Prof. Dr. Stefania Mitola

E-Mail Website
Guest Editor
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Interests: angiogenesis; membrane receptor; tumors; imaging; metabolism; bioscaffold for tissue regeneration
Special Issues, Collections and Topics in MDPI journals
Dr. Elisabetta Grillo

E-Mail Website
Co-Guest Editor
Unit of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Interests: mechanisms of tumorigenesis; cancer metabolism; tumor angiogenesis; receptor tyrosine kinases; novel anti-cancer agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tyrosine kinases are pleiotropic enzymes that mediate the signaling cascades occurring in response to both external and internal stimuli. They regulate critical cellular processes including cell survival, proliferation and differentiation; cell cycle control; cell metabolism; and cell migration. The activation mechanism for tyrosine kinases is highly conserved in evolution, which is expected for proteins exerting such critical roles. Genetic alterations of tyrosine kinases or abnormalities that alter their activity, abundance, regulation or spatiotemporal distribution are found in numerous human diseases. For example, the aberrant activation of tyrosine kinases has been causally linked to cancer, metabolic disorders, inflammation, arteriosclerosis and angiogenesis. On these bases, tyrosine kinase inhibitors have been developed to block their detrimental effects. However, a broad range of tyrosine kinases remain poorly characterized, and completing the picture is a major challenge for the future. Moreover, many orphan genetic alterations of tyrosine kinases may hide potential druggable targets. Additionally, obtaining mechanistic insights into the spatiotemporal regulation of the tyrosine kinase-mediated signaling network and its crosstalk with other signaling cascades is critical for developing effective treatments for human diseases driven by altered tyrosine kinases. This Special Issue aims to summarize the current knowledge and cutting-edge research on tyrosine kinases in human diseases. Reports can address both receptor and nonreceptor tyrosine kinases. In the latter case, we ask authors to focus on receptor crosstalk with other membrane proteins and heterodimerization as mechanisms for determining signaling specificity. Translational studies are particularly welcome. We also encourage authors to present noncanonical views in opinion papers or reviews.

Prof. Dr. Stefania Mitola
Guest Editor
Dr. Elisabetta Grillo
Co-Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mechanism of tyrosine kinase activation/inactivation in human diseases
  • mutations of tyrosine kinases in cancer
  • tyrosine kinases as therapeutic targets
  • novel therapeutic approaches to target tyrosine kinases

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Published Papers (3 papers)

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Research

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13 pages, 1778 KiB  
Article
A Cysteine Residue within the Kinase Domain of Zap70 Regulates Lck Activity and Proximal TCR Signaling
by Annika Schultz, Marvin Schnurra, Ali El-Bizri, Nadine M. Woessner, Sara Hartmann, Roland Hartig, Susana Minguet, Burkhart Schraven and Luca Simeoni
Cells 2022, 11(17), 2723; https://doi.org/10.3390/cells11172723 - 1 Sep 2022
Cited by 7 | Viewed by 2915
Abstract
Alterations in both the expression and function of the non-receptor tyrosine kinase Zap70 are associated with numerous human diseases including immunodeficiency, autoimmunity, and leukemia. Zap70 propagates the TCR signal by phosphorylating two important adaptor molecules, LAT and SLP76, which orchestrate the assembly of [...] Read more.
Alterations in both the expression and function of the non-receptor tyrosine kinase Zap70 are associated with numerous human diseases including immunodeficiency, autoimmunity, and leukemia. Zap70 propagates the TCR signal by phosphorylating two important adaptor molecules, LAT and SLP76, which orchestrate the assembly of the signaling complex, leading to the activation of PLCγ1 and further downstream pathways. These events are crucial to drive T-cell development and T-cell activation. Recently, it has been proposed that C564, located in the kinase domain of Zap70, is palmitoylated. A non-palmitoylable C564R Zap70 mutant, which has been reported in a patient suffering from immunodeficiency, is incapable of propagating TCR signaling and activating T cells. The lack of palmitoylation was suggested as the cause of this human disease. Here, we confirm that Zap70C564R is signaling defective, but surprisingly, the defective Zap70 function does not appear to be due to a loss in palmitoylation. We engineered a C564A mutant of Zap70 which, similarly to Zap70C564R, is non-palmitoylatable. However, this mutant was capable of propagating TCR signaling. Moreover, Zap70C564A enhanced the activity of Lck and increased its proximity to the TCR. Accordingly, Zap70-deficient P116 T cells expressing Zap70C564A displayed the hyperphosphorylation of TCR-ζ and Zap70 (Y319), two well-known Lck substrates. Collectively, these data indicate that C564 is important for the regulation of Lck activity and proximal TCR signaling, but not for the palmitoylation of Zap70. Full article
(This article belongs to the Special Issue New Insights into Tyrosine Kinase Alterations in Human Diseases)
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Review

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26 pages, 2197 KiB  
Review
Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease
by Kevin Kuonqui, Adana-Christine Campbell, Ananta Sarker, Arielle Roberts, Bracha L. Pollack, Hyeung Ju Park, Jinyeon Shin, Stav Brown, Babak J. Mehrara and Raghu P. Kataru
Cells 2024, 13(1), 68; https://doi.org/10.3390/cells13010068 - 28 Dec 2023
Cited by 8 | Viewed by 3250
Abstract
Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface [...] Read more.
Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface of lymphatic endothelial cells (LECs) and induce lymphatic proliferation, migration, and survival by activating intracellular PI3K-Akt and MAPK-ERK signaling pathways. Impaired lymphatic function and VEGFR3 signaling has been linked with a myriad of commonly encountered clinical conditions. This review provides a brief overview of intracellular VEGFR3 signaling in LECs and explores examples of dysregulated VEGFR3 signaling in various disease states, including (1) lymphedema, (2) tumor growth and metastasis, (3) obesity and metabolic syndrome, (4) organ transplant rejection, and (5) autoimmune disorders. A more complete understanding of the molecular mechanisms underlying the lymphatic pathology of each disease will allow for the development of novel strategies to treat these chronic and often debilitating illnesses. Full article
(This article belongs to the Special Issue New Insights into Tyrosine Kinase Alterations in Human Diseases)
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18 pages, 1451 KiB  
Review
Integrin Signaling Shaping BTK-Inhibitor Resistance
by Laura Polcik, Svenja Dannewitz Prosseda, Federico Pozzo, Antonella Zucchetto, Valter Gattei and Tanja Nicole Hartmann
Cells 2022, 11(14), 2235; https://doi.org/10.3390/cells11142235 - 18 Jul 2022
Cited by 6 | Viewed by 4085
Abstract
Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in cancer. Very late antigen-4 (VLA-4), a CD49d/CD29 heterodimer, is a beta1 integrin implicated [...] Read more.
Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in cancer. Very late antigen-4 (VLA-4), a CD49d/CD29 heterodimer, is a beta1 integrin implicated in therapy resistance in both solid tumors and haematological malignancies such as chronic lymphocytic leukemia (CLL). A complex inside-out signaling mechanism activates VLA-4, which might include several therapeutic targets for CLL. Treatment regimens for this disease have recently shifted towards novel agents targeting BCR signaling. Bruton’s tyrosine kinase (BTK) is a component of B cell receptor signaling and BTK inhibitors such as ibrutinib are highly successful; however, their limitations include indefinite drug administration, the development of therapy resistance, and toxicities. VLA-4 might be activated independently of BTK, resulting in an ongoing interaction of CD49d-expressing leukemic cells with their surrounding tissue, which may reduce the success of therapy with BTK inhibitors and increases the need for alternative therapies. In this context, we discuss the inside-out signaling cascade culminating in VLA-4 activation, consider the advantages and disadvantages of BTK inhibitors in CLL and elucidate the mechanisms behind cell adhesion-mediated drug resistance. Full article
(This article belongs to the Special Issue New Insights into Tyrosine Kinase Alterations in Human Diseases)
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