Special Issue "Protein Kinases and Cancers"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 February 2019)

Special Issue Editors

Guest Editor
Prof. Dr. Richard Bayliss

Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
Website | E-Mail
Interests: protein kinases; cell cycle; oncogenic gene fusions; structural biology; Myc
Co-Guest Editor
Dr. Sharon Yeoh

School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
E-Mail
Interests: Enzymology, enzyme kinetics

Special Issue Information

Dear Colleagues,

The regulation of protein function through phosphorylation is a major component of cellular signalling pathways, such as those that govern cell cycle progression, control gene expression or determine whether a cell survives or dies. In humans, the phosphorylation of proteins is catalysed by over 500 protein kinases, most of which specifically modify either Ser/Thr or Tyr side chains. Their catalytic activities are regulated through molecular mechanisms that are dysregulated in cancer by mutations that cause uncontrolled kinase activity. Tumours that harbour such mutations can be addicted to the activity of a single protein kinase, and kinase inhibitors have recently become a successful class of cancer therapeutic.

Despite rapid progress in the field of “Protein Kinases and Cancer”, opportunities remain for further developments that would transform our understanding of cancer and its treatment. For example, most research is focused on a small subset of human kinases and the biological functions of many cancer-relevant kinases have yet to be explored. This needs to be corrected if we are to fully exploit the potential of protein kinases in cancer therapy. A second example is the trend in drug discovery programmes towards developing approaches to overcome resistance to current therapeutics, such as allosteric kinase inhibitors. This innovative approach takes advantage of developments in our understanding of the structural mechanisms of kinase regulation.

We aim to stimulate discussion by bringing together expert opinion and new science from across the field in a Special Issue of Cancers. We welcome submissions that cover any relevant topic, including protein kinases and non-oncogene addiction; non-canonical protein kinases; protein kinase structure and dynamics; mechanisms of dysregulation in cancer; small molecule inhibitors of protein kinases; allostery in protein kinases; the future of protein kinase therapeutics.

Prof. Richard Bayliss
Dr. Sharon Yeoh
Guest Editors

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 papers will be 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. Cancers is an international peer-reviewed open access monthly 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 1800 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.

Published Papers (9 papers)

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Research

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Open AccessArticle Cyclin-Dependent Kinase 5 (CDK5)-Mediated Phosphorylation of Upstream Stimulatory Factor 2 (USF2) Contributes to Carcinogenesis
Cancers 2019, 11(4), 523; https://doi.org/10.3390/cancers11040523
Received: 10 February 2019 / Revised: 30 March 2019 / Accepted: 8 April 2019 / Published: 12 April 2019
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Abstract
The transcription factor USF2 is supposed to have an important role in tumor development. However, the regulatory mechanisms contributing to the function of USF2 are largely unknown. Cyclin-dependent kinase 5 (CDK5) seems to be of importance since high levels of CDK5 were found [...] Read more.
The transcription factor USF2 is supposed to have an important role in tumor development. However, the regulatory mechanisms contributing to the function of USF2 are largely unknown. Cyclin-dependent kinase 5 (CDK5) seems to be of importance since high levels of CDK5 were found in different cancers associated with high USF2 expression. Here, we identified USF2 as a phosphorylation target of CDK5. USF2 is phosphorylated by CDK5 at two serine residues, serine 155 and serine 222. Further, phosphorylation of USF2 at these residues was shown to stabilize the protein and to regulate cellular growth and migration. Altogether, these results delineate the importance of the CDK5-USF2 interplay in cancer cells. Full article
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Open AccessArticle New Phosphorylation Sites of Rad51 by c-Met Modulates Presynaptic Filament Stability
Cancers 2019, 11(3), 413; https://doi.org/10.3390/cancers11030413
Received: 15 February 2019 / Revised: 10 March 2019 / Accepted: 20 March 2019 / Published: 23 March 2019
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Abstract
Genomic instability through deregulation of DNA repair pathways can initiate cancer and subsequently result in resistance to chemo and radiotherapy. Understanding these biological mechanisms is therefore essential to overcome cancer. RAD51 is the central protein of the Homologous Recombination (HR) DNA repair pathway, [...] Read more.
Genomic instability through deregulation of DNA repair pathways can initiate cancer and subsequently result in resistance to chemo and radiotherapy. Understanding these biological mechanisms is therefore essential to overcome cancer. RAD51 is the central protein of the Homologous Recombination (HR) DNA repair pathway, which leads to faithful DNA repair of DSBs. The recombinase activity of RAD51 requires nucleofilament formation and is regulated by post-translational modifications such as phosphorylation. In the last decade, studies have suggested the existence of a relationship between receptor tyrosine kinases (RTK) and Homologous Recombination DNA repair. Among these RTK the c-MET receptor is often overexpressed or constitutively activated in many cancer types and its inhibition induces the decrease of HR. In this study, we show for the first time that c-MET is able to phosphorylate the RAD51 protein. We demonstrate in vitro that c-MET phosphorylates four tyrosine residues localized mainly in the subunit-subunit interface of RAD51. Whereas these post-translational modifications do not affect the presynaptic filament formation, they strengthen its stability against the inhibitor effect of the BRC peptide obtained from BRCA2. Taken together, these results confirm the role of these modifications in the regulation of the BRCA2-RAD51 interaction and underline the importance of c-MET in DNA damage response. Full article
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Open AccessArticle Effects of Antiangiogenetic Drugs on Microcirculation and Macrocirculation in Patients with Advanced-Stage Renal Cancer
Received: 16 November 2018 / Revised: 19 December 2018 / Accepted: 21 December 2018 / Published: 28 December 2018
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Abstract
Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching [...] Read more.
Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching for a relationship with possible causative factors in patients with metastatic renal cell carcinoma. We included 29 patients in a prospective, observational study; 22 were treated with a first-line drug (sunitinib), while seven participated in the second-line treatment (axitinib or cabozantinib). Patients were investigated at the beginning of antiangiogenic therapy (T0) and at one (T1), three (T2), and six months (T3) after treatment. Patients were evaluated by office blood pressure (BP) and ultrasonography to measure flow-mediated dilatation (FMD), and carotid artery distensibility (cDC) by echocardiography and nailfold capillaroscopy. Plasma endothelin-1 (p-ET-1), urine nitrates, and proteins were also measured. At T1, systolic BP, along with U proteins and p-ET-1, increased significantly. In patients with a clinically significant increase in BP (defined as either the need for an antihypertensive drug or systolic blood pressure (SBP) T1–T0 ≥10 and/or SBP ≥140 mmHg and/or diastolic blood pressure (DBP) T1–T0 ≥5 and/or DBP ≥90 mmHg), the urine nitrate concentration was lower at T0, whereas there were no differences in the p-ET-1 and U proteins. Seventeen participants showed changes in the capillaroscopic pattern at T1 with no association with BP increases. There were no differences in the FMD, cDC, and echocardiographic parameters. Our findings are consistent with those of previous studies about BP increases by TKI, and suggest a role of nitric oxide in BP maintenance in this population. Full article
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Review

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Open AccessReview Divergent Dynamics and Functions of ERK MAP Kinase Signaling in Development, Homeostasis and Cancer: Lessons from Fluorescent Bioimaging
Cancers 2019, 11(4), 513; https://doi.org/10.3390/cancers11040513
Received: 22 March 2019 / Revised: 8 April 2019 / Accepted: 8 April 2019 / Published: 10 April 2019
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Abstract
The extracellular signal-regulated kinase (ERK) signaling pathway regulates a variety of biological processes including cell proliferation, survival, and differentiation. Since ERK activation promotes proliferation of many types of cells, its deregulated/constitutive activation is among general mechanisms for cancer. Recent advances in bioimaging techniques [...] Read more.
The extracellular signal-regulated kinase (ERK) signaling pathway regulates a variety of biological processes including cell proliferation, survival, and differentiation. Since ERK activation promotes proliferation of many types of cells, its deregulated/constitutive activation is among general mechanisms for cancer. Recent advances in bioimaging techniques have enabled to visualize ERK activity in real-time at the single-cell level. Emerging evidence from such approaches suggests unexpectedly complex spatiotemporal dynamics of ERK activity in living cells and animals and their crucial roles in determining cellular responses. In this review, we discuss how ERK activity dynamics are regulated and how they affect biological processes including cell fate decisions, cell migration, embryonic development, tissue homeostasis, and tumorigenesis. Full article
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Open AccessReview Modelling of Protein Kinase Signaling Pathways in Melanoma and Other Cancers
Cancers 2019, 11(4), 465; https://doi.org/10.3390/cancers11040465
Received: 2 March 2019 / Revised: 26 March 2019 / Accepted: 30 March 2019 / Published: 3 April 2019
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Abstract
Melanoma is a highly aggressive tumor with a strong dependence on intracellular signaling pathways. Almost half of all melanomas are driven by mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) with BRAFV600E being the most prevalent mutation. [...] Read more.
Melanoma is a highly aggressive tumor with a strong dependence on intracellular signaling pathways. Almost half of all melanomas are driven by mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) with BRAFV600E being the most prevalent mutation. Recently developed targeted treatment directed against mutant BRAF and downstream mitogen-activated protein kinase (MAPK) MAP2K1 (also termed MEK1) have improved overall survival of melanoma patients. However, the MAPK signaling pathway is far more complex than a single chain of consecutively activated MAPK enzymes and it contains nested-, inherent feedback mechanisms, crosstalk with other signaling pathways, epigenetic regulatory mechanisms, and interacting small non-coding RNAs. A more complete understanding of this pathway is needed to better understand melanoma development and mechanisms of treatment resistance. Network reconstruction, analysis, and modelling under the systems biology paradigm have been used recently in different malignant tumors including melanoma to analyze and integrate ‘omics’ data, formulate mechanistic hypotheses on tumorigenesis, assess and personalize anticancer therapy, and propose new drug targets. Here we review the current knowledge of network modelling approaches in cancer with a special emphasis on melanoma. Full article
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Open AccessReview Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy
Cancers 2019, 11(4), 449; https://doi.org/10.3390/cancers11040449
Received: 12 February 2019 / Revised: 20 March 2019 / Accepted: 26 March 2019 / Published: 29 March 2019
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Abstract
Hedgehog (HH) signaling is an evolutionarily conserved pathway that is crucial for growth and tissue patterning during embryonic development. It is mostly quiescent in the adult, where it regulates tissue homeostasis and stem cell behavior. Aberrant reactivation of HH signaling has been associated [...] Read more.
Hedgehog (HH) signaling is an evolutionarily conserved pathway that is crucial for growth and tissue patterning during embryonic development. It is mostly quiescent in the adult, where it regulates tissue homeostasis and stem cell behavior. Aberrant reactivation of HH signaling has been associated to several types of cancer, including those in the skin, brain, prostate, breast and hematological malignancies. Activation of the canonical HH signaling is triggered by binding of HH ligand to the twelve-transmembrane protein PATCHED. The binding releases the inhibition of the seven-transmembrane protein SMOOTHENED (SMO), leading to its phosphorylation and activation. Hence, SMO activates the transcriptional effectors of the HH signaling, that belong to the GLI family of transcription factors, acting through a not completely elucidated intracellular signaling cascade. Work from the last few years has shown that protein kinases phosphorylate several core components of the HH signaling, including SMO and the three GLI proteins, acting as powerful regulatory mechanisms to fine tune HH signaling activities. In this review, we will focus on the mechanistic influence of protein kinases on HH signaling transduction. We will also discuss the functional consequences of this regulation and the possible implications for cancer therapy. Full article
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Open AccessReview Targeting Receptor Kinases in Colorectal Cancer
Cancers 2019, 11(4), 433; https://doi.org/10.3390/cancers11040433
Received: 16 February 2019 / Revised: 19 March 2019 / Accepted: 25 March 2019 / Published: 27 March 2019
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Abstract
Colorectal cancer is the third most common malignancy in men and the second most common cancer in women. Despite the success of screening programs and the development of adjuvant therapies, the global burden of colorectal cancer is expected to increase by 60% to [...] Read more.
Colorectal cancer is the third most common malignancy in men and the second most common cancer in women. Despite the success of screening programs and the development of adjuvant therapies, the global burden of colorectal cancer is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030. In recent years, a great effort has been made to demonstrate the utility of protein kinase inhibitors for cancer treatment. Considering this heterogeneous disease is defined by mutations that activate different Receptor Tyrosine Kinases (RTKs) and affect downstream components of RTK-activated transduction pathways, in this review we analyze the potential utility of different kinase inhibitors for colorectal cancer treatment. Full article
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Open AccessReview The Role of M3 Muscarinic Receptor Ligand-Induced Kinase Signaling in Colon Cancer Progression
Cancers 2019, 11(3), 308; https://doi.org/10.3390/cancers11030308
Received: 7 February 2019 / Revised: 22 February 2019 / Accepted: 27 February 2019 / Published: 5 March 2019
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Abstract
Despite a reduction in incidence over the past decade, colon cancer remains the second most common cause of cancer death in the United States; recent demographics suggest this disease is now afflicting younger persons. M3 muscarinic receptor (M3R) mRNA and [...] Read more.
Despite a reduction in incidence over the past decade, colon cancer remains the second most common cause of cancer death in the United States; recent demographics suggest this disease is now afflicting younger persons. M3 muscarinic receptor (M3R) mRNA and protein are over-expressed in colon cancer, and M3R can be activated by both traditional (e.g., acetylcholine) and non-traditional (e.g., bile acids) muscarinic ligands. In this review, we weigh the data supporting a prominent role for key protein kinases downstream of M3R activation in promoting colon cancer progression and dissemination. Specifically, we explore the roles that downstream activation of the mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK), protein kinase C, p38 MAPK, and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways play in mediating colon cancer cell proliferation, survival, migration and invasion. We assess the impact of M3R-stimulated induction of selected matrix metalloproteinases germane to these hallmarks of colon cancer progression. In this context, we also critically review the reproducibility of findings derived from a variety of in vivo and in vitro colon cancer models, and their fidelity to human disease. Finally, we summarize the therapeutic potential of targeting various steps from ligand-M3R interaction to the activation of key downstream molecules. Full article
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Open AccessReview The Enigmatic Protein Kinase C-eta
Cancers 2019, 11(2), 214; https://doi.org/10.3390/cancers11020214
Received: 17 January 2019 / Revised: 4 February 2019 / Accepted: 10 February 2019 / Published: 13 February 2019
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Abstract
Protein kinase C (PKC), a multi-gene family, plays critical roles in signal transduction and cell regulation. Protein kinase C-eta (PKCη) is a unique member of the PKC family since its regulation is distinct from other PKC isozymes. PKCη was shown to regulate cell [...] Read more.
Protein kinase C (PKC), a multi-gene family, plays critical roles in signal transduction and cell regulation. Protein kinase C-eta (PKCη) is a unique member of the PKC family since its regulation is distinct from other PKC isozymes. PKCη was shown to regulate cell proliferation, differentiation and cell death. It was also shown to contribute to chemoresistance in several cancers. PKCη has been associated with several cancers, including renal cell carcinoma, glioblastoma, breast cancer, non-small cell lung cancer, and acute myeloid leukemia. However, mice lacking PKCη were more susceptible to tumor formation in a two-stage carcinogenesis model, and it is downregulated in hepatocellular carcinoma. Thus, the role of PKCη in cancer remains controversial. The purpose of this review article is to discuss how PKCη regulates various cellular processes that may contribute to its contrasting roles in cancer. Full article
(This article belongs to the Special Issue Protein Kinases and Cancers)
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