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Protein Kinases: Signalling and Disease

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

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 57903

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Prof. John Siekierka

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Sokol Institute for Pharmaceutical Life Sciences and Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, USA
Interests: protein kinase signaling; protein kinases as therapeutic targets; parasitic protein kinases

Special Issue Information

Dear Colleagues,

Protein kinases have become a major drug target for the treatment of a variety of diseases, especially cancer. Kinase inhibitors have been approved for a number of therapeutic indications and will likely continue to expand. One recent example is the small molecule JAK kinase inhibitor, Xeljanz (tofacitinib). Originally approved for the treatment of rheumatoid arthritis in 2012, it has received approval this year (2018) the treatment of ulcerative colitis as well. The list of indications for which kinase inhibitors may find use as therapeutic agents continues to grow, including uses for treating viral and parasitic diseases. This Special Issue focuses on the connection between protein kinase signalling and disease, with an emphasis on novel small molecule inhibitors and new therapeutic indications for these agents.

Prof. John Siekierka
Guest Editor

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Keywords

protein kinases
small molecule inhibitors
novel indications

Published Papers (10 papers)

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Research

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15 pages, 2693 KiB

Open AccessArticle

Glycogen Synthase Kinase-3β Facilitates Cytokine Production in 12-O-Tetradecanoylphorbol-13-Acetate/Ionomycin-Activated Human CD4⁺ T Lymphocytes

by Cheng-Chieh Tsai, Chin-Kun Tsai, Po-Chun Tseng, Chiou-Feng Lin and Chia-Ling Chen

Cells 2020, 9(6), 1424; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061424 - 08 Jun 2020

Cited by 3 | Viewed by 2429

Abstract

Cytokines are the major immune regulators secreted from activated CD4⁺ T lymphocytes that activate adaptive immunity to eradicate nonself cells, including pathogens, tumors, and allografts. The regulation of glycogen synthase kinase (GSK)-3β, a serine/threonine kinase, controls cytokine production by regulating transcription factors. The artificial in vitro activation of CD4⁺ T lymphocytes by a combination of 12-O-tetradecanoylphorbol-13-acetate and ionomycin, the so-called T/I model, led to an inducible production of cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-2. As demonstrated by the approaches of pharmacological targeting and genetic knockdown of GSK-3β, T/I treatment effectively caused GSK-3β activation followed by GSK-3β-regulated cytokine production. In contrast, pharmacological inhibition of the proline-rich tyrosine kinase 2 and calcineurin signaling pathways blocked cytokine production, probably by deactivating GSK-3β. The blockade of GSK-3β led to the inhibition of the nuclear translocation of T-bet, a vital transcription factor of T lymphocyte cytokines. In a mouse model, treatment with the GSK-3β inhibitor 6-bromoindirubin-3’-oxime significantly inhibited T/I-induced mortality and serum cytokine levels. In summary, targeting GSK-3β effectively inhibits CD4⁺ T lymphocyte activation and cytokine production. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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17 pages, 4704 KiB

Open AccessArticle

CCN2 Mediates S1P-Induced Upregulation of COX2 Expression in Human Granulosa-Lutein Cells

by Liao-Liao Hu, Hsun-Ming Chang, Yuyin Yi, Yingtao Liu, Elizabeth L. Taylor, Li-Ping Zheng and Peter C.K. Leung

Cells 2019, 8(11), 1445; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8111445 - 15 Nov 2019

Cited by 5 | Viewed by 4128

Abstract

CCN1 and CCN2 are members of the CCN family and play essential roles in the regulation of multiple female reproductive functions, including ovulation. Cyclooxygenase-2 (COX2) is a critical mediator of ovulation and can be induced by sphingosine-1-phosphate (S1P) through the S1P_1/3-mediated Yes-associated protein (YAP) signaling. However, it is unclear whether CCN1 or CCN2 can mediate S1P-induced upregulation of COX2 expression and increase in prostaglandin E2 (PGE2) production in human granulosa-lutein (hGL) cells. In the present study, we investigated the effects of S1P on the expressions of CCN1 and CCN2 in hGL cells. Additionally, we used a dual inhibition approach (siRNA-mediated silencing and small molecular inhibitors) to investigate the molecular mechanisms of S1P effects. Our results showed that S1P treatment significantly upregulated the expression of CCN1 and CCN2 in a concentration-dependent manner in hGL cells. Additionally, inhibition or silencing of S1P₁, but not S1P₃, completely abolished the S1P-induced upregulation of CCN2 expression. Furthermore, we demonstrated that S1P-induced nuclear translocation of YAP and inhibition or silencing of YAP completely abolished the S1P-induced upregulation of CCN1 and CCN2 expression. Notably, silencing of CCN2, but not CCN1, completely reversed the S1P-induced upregulation of COX2 expression and the increase in PGE2 production. Thus, CCN2 mediates the S1P-induced upregulation of COX2 expression through the S1P₁-mediated signaling pathway in hGL cells. Our findings expand our understanding of the molecular mechanism underlying the S1P-mediated cellular activities in the human ovary. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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19 pages, 3699 KiB

Open AccessArticle

ATM Regulated PTEN Degradation Is XIAP E3 Ubiquitin Ligase Mediated in p85α Deficient Cancer Cells and Influence Platinum Sensitivity

by Reem Ali, Muslim Alabdullah, Islam Miligy, Makhliyo Normatova, Roya Babaei-Jadidi, Abdolrahman S. Nateri, Emad A. Rakha and Srinivasan Madhusudan

Cells 2019, 8(10), 1271; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101271 - 18 Oct 2019

Cited by 11 | Viewed by 4615

Abstract

Ataxia-telegiectasia mutated (ATM), phosphatase and tensin homolog (PTEN), and p85α are key tumour suppressors. Whether ATM regulates PTEN expression and influence platinum sensitivity is unknown. We generated ATM knockdowns (KD) and CRISPR knock outs (KO) in glioblastoma (LN18, LN229) and ovarian cancer cells (OVCAR3, OVCAR4). Doxycycline inducible PTEN expression was generated in LN18 and LN229 cells. Transient KD of p85α, CK2, and XIAP was accomplished using siRNAs. Stable p85α knock-in was isolated in LN18 cells. Molecular biology assays included proteasome activity assays, PCR, flow cytometry analysis (cell cycle, double strand break accumulation, apoptosis), immunofluorescence, co-immunoprecipitation, clonogenic, invasion, migration, and 3D neurosphere assays. The clinicopathological significance of ATM, PTEN, p85α, and XIAP (X-linked inhibitor of apoptosis protein) was evaluated in 525 human ovarian cancers using immunohistochemistry. ATM regulated PTEN is p85α dependant. ATM also controls CK2α level which in turn phosphorylates and stabilizes PTEN. In addition, p85α physically interacts with CK2α and protects CK2α from ATM regulated degradation. ATM deficiency resulted in accumulation of XIAP/p-XIAP levels which ubiquitinated PTEN and CK2α thereby directing them to degradation. ATM depletion in the context of p85α deficiency impaired cancer cell migration and invasion reduced 3D-neurosphere formation and increased toxicity to cisplatin chemotherapy. Increased sensitivity to platinum was associated with DNA double strand breaks accumulation, cell cycle arrest, and induction of autophagy. In ovarian cancer patients, ATM, PTEN, p85α, and XIAP protein levels predicted better progression free survival after platinum therapy. We unravel a previously unknown function of ATM in the regulation of PTEN throμgh XIAP mediated proteasome degradation. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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20 pages, 5156 KiB

Open AccessArticle

Skeletal Muscle Response to Deflazacort, Dexamethasone and Methylprednisolone

by Alan Fappi, Juliana de Carvalho Neves, Leandro Nunes Sanches, Pedro Victor Massaroto e Silva, Guilherme Yuiti Sikusawa, Thayane Pereira Correa Brandão, Gerson Chadi and Edmar Zanoteli

Cells 2019, 8(5), 406; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050406 - 01 May 2019

Cited by 25 | Viewed by 6224

Abstract

Glucocorticoids represent some of the most prescribed drugs that are widely used in the treatment of neuromuscular diseases, but their usage leads to side effects such as muscle atrophy. However, different synthetic glucocorticoids can lead to different muscle effects, depending upon its chemical formulation. Here, we intended to demonstrate the muscle histologic and molecular effects of administering different glucocorticoids in equivalency and different dosages. Methods: Seventy male Wistar rats distributed into seven groups received different glucocorticoids in equivalency for ten days or saline solution. The study groups were: Control group (CT) saline solution; dexamethasone (DX) 1.25 or 2.5 mg/kg/day; methylprednisolone (MP) 6.7 or 13.3mg/kg/day; and deflazacort (DC) 10 or 20 mg/kg/day. At the end of the study, the animals were euthanized, and the tibialis anterior and gastrocnemius muscles were collected for metachromatic ATPase (Cross-sectional area (CSA) measurement), Western blotting (protein expression of IGF-1 and Ras/Raf/MEK/ERK pathways) and RT-PCR (MYOSTATIN, MuRF-1, Atrogin-1, REDD-1, REDD-2, MYOD, MYOG and IRS1/2 genes expression) experiments. Results: Muscle atrophy occurred preferentially in type 2B fibers in all glucocorticoid treated groups. DC on 10 mg/kg/day was less harmful to type 2B fibers CSA than other doses and types of synthetic glucocorticoids. In type 1 fibers CSA, lower doses of DC and DX were more harmful than high doses. DX had a greater effect on the IGF-1 pathway than other glucocorticoids. MP more significantly affected P-ERK1/2 expression, muscle fiber switching (fast-to-slow), and expression of REDD1 and MyoD genes than other glucocorticoids. Compared to DX and MP, DC had less of an effect on the expression of atrogenes (MURF-1 and Atrogin-1) despite increased MYOSTATIN and decreased IRS-2 genes expression. Conclusions: Different glucocorticoids appears to cause muscle atrophy affecting secondarily different signaling mechanisms. MP is more likely to affect body/muscles mass, MEK/ERK pathway and fiber type transition, DX the IGF-1 pathway and IRS1/2 expression. DC had the smallest effect on muscle atrophic response possibly due a delayed timing on atrogenes response. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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16 pages, 4678 KiB

Open AccessArticle

Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies

by Shailima Rampogu, Ayoung Baek, Chanin Park, Minky Son, Shraddha Parate, Saravanan Parameswaran, Yohan Park, Baji Shaik, Ju Hyun Kim, Seok Ju Park and Keun Woo Lee

Cells 2019, 8(3), 269; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8030269 - 21 Mar 2019

Cited by 15 | Viewed by 3867

Abstract

Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discovering new anti-angiogenic inhibitors that target the signalling pathways. To obtain this objective, a structure-based pharmacophore model was built from the drug target VEGFR-2 (PDB code: 4AG8), complexed with axitinib and was subsequently validated and employed as a 3D query to retrieve the candidate compounds with the key inhibitory features. The model was escalated to molecular docking studies resulting in seven candidate compounds. The molecular docking studies revealed that the seven compounds displayed a higher dock score than the reference-cocrystallised compound. The GROningen MAchine for Chemical Simulations (GROMACS) package guided molecular dynamics (MD) results determined their binding mode and affirmed stable root mean square deviation. Furthermore, these compounds have preserved their key interactions with the residues Glu885, Glu917, Cys919 and Asp1046. The obtained findings deem that the seven compounds could act as novel anti-angiogenic inhibitors and may further assist as the prototype in designing and developing new inhibitors. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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14 pages, 2740 KiB

Open AccessArticle

Mechanisms of TQ-6, a Novel Ruthenium-Derivative Compound, against Lipopolysaccharide-Induced In Vitro Macrophage Activation and Liver Injury in Experimental Mice: The Crucial Role of p38 MAPK and NF-κB Signaling

by Chih-Hsuan Hsia, Marappan Velusamy, Thanasekaran Jayakumar, Yen-Jen Chen, Chih-Wei Hsia, Jie-Heng Tsai, Ruei-Dun Teng and Joen-Rong Sheu

Cells 2018, 7(11), 217; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7110217 - 19 Nov 2018

Cited by 11 | Viewed by 4208

Abstract

Several studies have reported that metal complexes exhibit anti-inflammatory activities; however, the molecular mechanism is not well understood. In this study, we used a potent ruthenium (II)-derived compound, [Ru(η6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), to investigate the molecular mechanisms underlying the anti-inflammatory effects against lipopolysaccharide (LPS)-induced macrophage activation and liver injury in mice. Treating LPS-stimulated RAW 264.7 cells with TQ-6 suppressed nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner. The LPS-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) were reduced in TQ-6-treated cells. TQ-6 suppressed, LPS-stimulated p38 MAPK phosphorylation, IκBα degradation, and p65 nuclear translocation in cells. Consistent with the in vitro studies, TQ-6 also suppressed the expression of iNOS, TNF-α, and p65 in the mouse model with acute liver injury induced by LPS. The present study showed that TQ-6 could protect against LPS-induced in vitro inflammation in macrophage and in vivo liver injury in mice, and suggested that NF-κB could be a promising target for protecting against LPS-induced inflammation and liver injury by TQ-6. Therefore, TQ-6 can be a potential therapeutic agent for treating inflammatory diseases. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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Review

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28 pages, 3060 KiB

Open AccessReview

Protein Kinase C Isozymes and Autophagy during Neurodegenerative Disease Progression

by Humeyra Nur Kaleli, Ebru Ozer, Veysel Ogulcan Kaya and Ozlem Kutlu

Cells 2020, 9(3), 553; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030553 - 27 Feb 2020

Cited by 21 | Viewed by 6661

Abstract

Protein kinase C (PKC) isozymes are members of the Serine/Threonine kinase family regulating cellular events following activation of membrane bound phospholipids. The breakdown of the downstream signaling pathways of PKC relates to several disease pathogeneses particularly neurodegeneration. PKC isozymes play a critical role in cell death and survival mechanisms, as well as autophagy. Numerous studies have reported that neurodegenerative disease formation is caused by failure of the autophagy mechanism. This review outlines PKC signaling in autophagy and neurodegenerative disease development and introduces some polyphenols as effectors of PKC isozymes for disease therapy. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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22 pages, 2565 KiB

Open AccessReview

The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

by Maria A. Lanuza, Laia Just-Borràs, Erica Hurtado, Víctor Cilleros-Mañé, Marta Tomàs, Neus Garcia and Josep Tomàs

Cells 2019, 8(12), 1578; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121578 - 05 Dec 2019

Cited by 27 | Viewed by 5440

Abstract

Brain-derived neurotrophic factor (BDNF) promotes neuron survival in adulthood in the central nervous system. In the peripheral nervous system, BDNF is a contraction-inducible protein that, through its binding to tropomyosin-related kinase B receptor (TrkB), contributes to the retrograde neuroprotective control done by muscles, which is necessary for motor neuron function. BDNF/TrkB triggers downstream presynaptic pathways, involving protein kinase C, essential for synaptic function and maintenance. Undeniably, this reciprocally regulated system exemplifies the tight communication between nerve terminals and myocytes to promote synaptic function and reveals a new view about the complementary and essential role of pre and postsynaptic interplay in keeping the synapse healthy and strong. This signaling at the neuromuscular junction (NMJ) could establish new intervention targets across neuromuscular diseases characterized by deficits in presynaptic activity and muscle contractility and by the interruption of the connection between nervous and muscular tissues, such as amyotrophic lateral sclerosis (ALS). Indeed, exercise and other therapies that modulate kinases are effective at delaying ALS progression, preserving NMJs and maintaining motor function to increase the life quality of patients. Altogether, we review synaptic activity modulation of the BDNF/TrkB/PKC signaling to sustain NMJ function, its and other kinases’ disturbances in ALS and physical and molecular mechanisms to delay disease progression. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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20 pages, 1802 KiB

Open AccessReview

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

by Jing Chen, Renate Kos, Johan Garssen and Frank Redegeld

Cells 2019, 8(12), 1486; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121486 - 21 Nov 2019

Cited by 109 | Viewed by 12454

Abstract

Necroptosis, or regulated necrosis, is an important type of programmed cell death in addition to apoptosis. Necroptosis induction leads to cell membrane disruption, inflammation and vascularization. It plays important roles in various pathological processes, including neurodegeneration, inflammatory diseases, multiple cancers, and kidney injury. The molecular regulation of necroptotic pathway has been intensively studied in recent years. Necroptosis can be triggered by multiple stimuli and this pathway is regulated through activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and pseudokinase mixed lineage kinase domain-like (MLKL). A better understanding of the mechanism of regulation of necroptosis will further aid to the development of novel drugs for necroptosis-associated human diseases. In this review, we focus on new insights in the regulatory machinery of necroptosis. We further discuss the role of necroptosis in different pathologies, its potential as a therapeutic target and the current status of clinical development of drugs interfering in the necroptotic pathway. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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27 pages, 2141 KiB

Open AccessReview

Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link

by Chaobo Chen, Leonard J. Nelson, Matías A. Ávila and Francisco Javier Cubero

Cells 2019, 8(10), 1172; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101172 - 28 Sep 2019

Cited by 30 | Viewed by 7176

Abstract

In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low—a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA. Full article

(This article belongs to the Special Issue Protein Kinases: Signalling and Disease)

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