Submit to Cancers Review for Cancers Propose a Special Issue

Journal Browser

► Journal Browser

Protein Kinases and Cancers

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Published Papers

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

Deadline for manuscript submissions: closed (15 February 2019) | Viewed by 55711

Share This Special Issue

Special Issue Editors

Prof. Dr. Richard Bayliss

E-Mail Website
Guest Editor

Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
Interests: protein kinases; cell cycle; oncogenic gene fusions; structural biology; Myc
Special Issues, Collections and Topics in MDPI journals

Dr. Sharon Yeoh

E-Mail Website
Co-Guest Editor

School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
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 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. Cancers 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 2900 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 (12 papers)

Download All Papers

Research

Jump to: Review

12 pages, 935 KiB

Open AccessArticle

The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax

by Chiara Tarantelli, Eugenio Gaudio, Petra Hillmann, Filippo Spriano, Giulio Sartori, Luca Aresu, Luciano Cascione, Denise Rageot, Ivo Kwee, Florent Beaufils, Emanuele Zucca, Anastasios Stathis, Matthias P. Wymann, Vladimir Cmiljanovic, Doriano Fabbro and Francesco Bertoni

Cancers 2019, 11(6), 775; https://doi.org/10.3390/cancers11060775 - 04 Jun 2019

Cited by 14 | Viewed by 4135

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling cascade is an important therapeutic target for lymphomas. Rapamycin-derivates as allosteric mTOR complex 1 (TORC1) inhibitors have shown moderate preclinical and clinical anti-lymphoma activity. Here, we assessed the anti-tumor activity of PQR620, a novel brain penetrant dual TORC1/2 inhibitor, in 56 lymphoma cell lines. We observed anti-tumor activity across 56 lymphoma models with a median IC₅₀ value of 250 nM after 72 h of exposure. PQR620 was largely cytostatic, but the combination with the BCL2 inhibitor venetoclax led to cytotoxicity. Both the single agent and the combination data were validated in xenograft models. The data support further evaluation of PQR620 as a single agent or in combination with venetoclax. Full article

(This article belongs to the Special Issue Protein Kinases and Cancers)

► Show Figures

Figure 1

14 pages, 1575 KiB

Open AccessArticle

Differential Activation of ERK Signaling in HPV-Related Oropharyngeal Squamous Cell Carcinoma

by Chao Rong, Marie Muller, Christa Flechtenmacher, Dana Holzinger, Gerhard Dyckhoff, Olcay Cem Bulut, Dominik Horn, Peter Plinkert, Jochen Hess and Annette Affolter

Cancers 2019, 11(4), 584; https://doi.org/10.3390/cancers11040584 - 25 Apr 2019

Cited by 13 | Viewed by 4001

Abstract

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) forms a distinct tumor entity with better survival clinical outcome. Numerous underlying molecular mechanisms have been postulated for differences in treatment response, but the impact of MEK/ERK signaling, a main driver of carcinogenesis in various cancers including OPSCC and key player mediating therapy resistance remains elusive. In a retrospective experimental cohort study, primary tumor samples from OPSCC patients (n = 124) were available on tissue microarrays (TMAs) and expression levels of phosphorylated ERK1/2 (pERK1/2) were detected by immunohistochemical staining. Correlations of pERK1/2 expression patterns with clinicopathological features and clinical outcome were evaluated by statistical analysis. A low pERK1/2 expression was strongly associated with HPV-related OPSCC, while primary tumors with high pERK1/2 staining showed a distinctly worse survival outcome and were associated with higher cellular differentiation. Co-activation of both ERK1/2 and AKT was a common event and was associated with unfavorable prognosis in our cohort. However, the combinatorial analysis of pAKT (Ser473) and pERK1/2 did not strengthen the predictive power of pERK1/2, suggesting that pERK1/2 plays a more significant function in OPSCC. In summary, our data provide a compelling experimental and statistical evidence that low levels of tumor cell intrinsic ERK1/2 activation contribute at least in part to the favorable outcome of HPV-related OPSCC. On the other hand, presented findings indicate that non-HPV-related OPSCC with elevated ERK phosphorylation are at high risk for treatment failure and might benefit from targeted therapy of MEK/ERK signaling. Full article

(This article belongs to the Special Issue Protein Kinases and Cancers)

► Show Figures

Figure 1

14 pages, 1357 KiB

Open AccessArticle

Cyclin-Dependent Kinase 5 (CDK5)-Mediated Phosphorylation of Upstream Stimulatory Factor 2 (USF2) Contributes to Carcinogenesis

by Tabughang Franklin Chi, Tina Horbach, Claudia Götz, Thomas Kietzmann and Elitsa Y. Dimova

Cancers 2019, 11(4), 523; https://doi.org/10.3390/cancers11040523 - 12 Apr 2019

Cited by 18 | Viewed by 3655

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 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)

► Show Figures

Figure 1

19 pages, 5002 KiB

Open AccessArticle

New Phosphorylation Sites of Rad51 by c-Met Modulates Presynaptic Filament Stability

by Thomas Chabot, Alain Defontaine, Damien Marquis, Axelle Renodon-Corniere, Emmanuelle Courtois, Fabrice Fleury and Yvonnick Cheraud

Cancers 2019, 11(3), 413; https://doi.org/10.3390/cancers11030413 - 23 Mar 2019

Cited by 10 | Viewed by 4621

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, 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)

► Show Figures

Figure 1

15 pages, 2638 KiB

Open AccessArticle

Effects of Antiangiogenetic Drugs on Microcirculation and Macrocirculation in Patients with Advanced-Stage Renal Cancer

by Andrea Dalbeni, Chiara Ciccarese, Michele Bevilacqua, Marco Benati, Cristian Caimmi, Luca Cerrito, Federico Famà, Roberto Iacovelli, Anna Mantovani, Francesco Massari Alessandra Meneguzzi, Pietro Minuz, Martina Montagnana, Giovanni Orsolini, Maurizio Rossini, Gianpaolo Tortora, Ombretta Viapiana and Cristiano Fava

Cancers 2019, 11(1), 30; https://doi.org/10.3390/cancers11010030 - 28 Dec 2018

Cited by 7 | Viewed by 3001

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 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)

► Show Figures

Figure 1

Review

Jump to: Research

13 pages, 920 KiB

Open AccessReview

Smad7 and Colorectal Carcinogenesis: A Double-Edged Sword

by Edoardo Troncone and Giovanni Monteleone

Cancers 2019, 11(5), 612; https://doi.org/10.3390/cancers11050612 - 01 May 2019

Cited by 18 | Viewed by 4159

Abstract

Colorectal carcinogenesis is a complex process in which many immune and non-immune cells and a huge number of mediators are involved. Among these latter factors, Smad7, an inhibitor of the transforming growth factor (TGF)-β1 signaling that has been involved in the amplification of the inflammatory process sustaining chronic intestinal inflammation, is supposed to make a valid contribution to the growth and survival of colorectal cancer (CRC) cells. Smad7 is over-expressed by tumoral cells in both sporadic CRC and colitis-associated CRC, where it sustains neoplastic processes through activation of either TGFβ-dependent or non-dependent pathways. Consistently, genome-wide association studies have identified single nucleotide polymorphisms of the Smad7 gene associated with CRC and shown that either amplification or deletion of the Smad7 gene associates with a poor prognosis or better outcome, respectively. On the other hand, there is evidence that over-expression of Smad7 in immune cells infiltrating the inflamed gut of patients with inflammatory bowel disease can elicit anti-tumor responses, with the down-stream effect of attenuating CRC cell growth. Taken together, these observations suggest a double role of Smad7 in colorectal carcinogenesis, which probably depends on the cell subset and the biological context analyzed. In this review, we summarize the available evidences about the role of Smad7 in both sporadic and colitis-associated CRC. Full article

(This article belongs to the Special Issue Protein Kinases and Cancers)

► Show Figures

Figure 1

11 pages, 1088 KiB

Open AccessReview

Divergent Dynamics and Functions of ERK MAP Kinase Signaling in Development, Homeostasis and Cancer: Lessons from Fluorescent Bioimaging

by Yu Muta, Michiyuki Matsuda and Masamichi Imajo

Cancers 2019, 11(4), 513; https://doi.org/10.3390/cancers11040513 - 10 Apr 2019

Cited by 21 | Viewed by 5960

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 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)

► Show Figures

Figure 1

18 pages, 2327 KiB

Open AccessReview

Modelling of Protein Kinase Signaling Pathways in Melanoma and Other Cancers

by Manfred Kunz and Julio Vera

Cancers 2019, 11(4), 465; https://doi.org/10.3390/cancers11040465 - 03 Apr 2019

Cited by 15 | Viewed by 5623

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. 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)

► Show Figures

Figure 1

23 pages, 932 KiB

Open AccessReview

Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy

by Valentina Montagnani and Barbara Stecca

Cancers 2019, 11(4), 449; https://doi.org/10.3390/cancers11040449 - 29 Mar 2019

Cited by 37 | Viewed by 5943

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 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)

► Show Figures

Figure 1

24 pages, 506 KiB

Open AccessReview

Targeting Receptor Kinases in Colorectal Cancer

by Marilina García-Aranda and Maximino Redondo

Cancers 2019, 11(4), 433; https://doi.org/10.3390/cancers11040433 - 27 Mar 2019

Cited by 47 | Viewed by 5094

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 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)

► Show Figures

Figure 1

13 pages, 378 KiB

Open AccessReview

The Role of M3 Muscarinic Receptor Ligand-Induced Kinase Signaling in Colon Cancer Progression

by Mazen Tolaymat, Shannon M. Larabee, Shien Hu, Guofeng Xie and Jean-Pierre Raufman

Cancers 2019, 11(3), 308; https://doi.org/10.3390/cancers11030308 - 05 Mar 2019

Cited by 22 | Viewed by 4575

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 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)

► Show Figures

Figure 1

12 pages, 602 KiB

Open AccessReview

The Enigmatic Protein Kinase C-eta

by Alakananda Basu

Cancers 2019, 11(2), 214; https://doi.org/10.3390/cancers11020214 - 13 Feb 2019

Cited by 10 | Viewed by 3979

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 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)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Protein Kinases and Cancers

Share This Special Issue

Special Issue Editors

Special Issue Information

Published Papers (12 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI