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18 pages, 2928 KiB

Open AccessArticle

Blockade of EGFR Activation Promotes TNF-Induced Lung Epithelial Cell Apoptosis and Pulmonary Injury

by Toshimitsu Yamaoka, Satoru Arata, Mayumi Homma, Tetsuya Homma, Sojiro Kusumoto, Koichi Ando, Ryou Manabe, Yasunari Kishino, Motoi Ohba, Junji Tsurutani, Masafumi Takimoto, Tohru Ohmori and Hironori Sagara

Int. J. Mol. Sci. 2019, 20(16), 4021; https://doi.org/10.3390/ijms20164021 - 17 Aug 2019

Cited by 25 | Viewed by 5034

Abstract

Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis [...] Read more.

Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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25 pages, 3741 KiB

Open AccessArticle

The Protective Effect of Insulin on Rat Cortical Neurons in Oxidative Stress and Its Dependence on the Modulation of Akt, GSK-3beta, ERK1/2, and AMPK Activities

by Irina O. Zakharova, Tatiana V. Sokolova, Liubov V. Bayunova, Inna I. Zorina, Maria P. Rychkova, Alexander O. Shpakov and Natalia F. Avrova

Int. J. Mol. Sci. 2019, 20(15), 3702; https://doi.org/10.3390/ijms20153702 - 29 Jul 2019

Cited by 23 | Viewed by 4030

Abstract

Insulin is a promising drug for the treatment of diseases associated with brain damage. However, the mechanism of its neuroprotective action is far from being understood. Our aim was to study the insulin-induced protection of cortical neurons in oxidative stress and its mechanism. [...] Read more.

Insulin is a promising drug for the treatment of diseases associated with brain damage. However, the mechanism of its neuroprotective action is far from being understood. Our aim was to study the insulin-induced protection of cortical neurons in oxidative stress and its mechanism. Immunoblotting, flow cytometry, colorimetric, and fluorometric techniques were used. The insulin neuroprotection was shown to depend on insulin concentration in the nanomolar range. Insulin decreased the reactive oxygen species formation in neurons. The insulin-induced modulation of various protein kinase activities was studied at eight time-points after neuronal exposure to prooxidant (hydrogen peroxide). In prooxidant-exposed neurons, insulin increased the phosphorylation of GSK-3beta at Ser⁹ (thus inactivating it), which resulted from Akt activation. Insulin activated ERK1/2 in neurons 5–30 min after cell exposure to prooxidant. Hydrogen peroxide markedly activated AMPK, while it was for the first time shown that insulin inhibited it in neurons at periods of the most pronounced activation by prooxidant. Insulin normalized Bax/Bcl-2 ratio and mitochondrial membrane potential in neurons in oxidative stress. The inhibitors of the PI3K/Akt and MEK1/2/ERK1/2 signaling pathways and the AMPK activator reduced the neuroprotective effect of insulin. Thus, the protective action of insulin on cortical neurons in oxidative stress appear to be realized to a large extent through activation of Akt and ERK1/2, GSK-3beta inactivation, and inhibition of AMPK activity increased by neuronal exposure to prooxidant. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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14 pages, 2617 KiB

Open AccessArticle

Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells

by Kiyohiro Ando, Yohko Nakamura, Hiroki Nagase, Akira Nakagawara, Tsugumichi Koshinaga, Satoshi Wada and Makoto Makishima

Int. J. Mol. Sci. 2019, 20(15), 3700; https://doi.org/10.3390/ijms20153700 - 29 Jul 2019

Cited by 14 | Viewed by 6133

Abstract

Checkpoint kinase 1 (CHK1) is a central mediator of the DNA damage response (DDR) at the S and G2/M cell cycle checkpoints, and plays a crucial role in preserving genomic integrity. CHK1 overexpression is thought to contribute to cancer aggressiveness, and several selective [...] Read more.

Checkpoint kinase 1 (CHK1) is a central mediator of the DNA damage response (DDR) at the S and G2/M cell cycle checkpoints, and plays a crucial role in preserving genomic integrity. CHK1 overexpression is thought to contribute to cancer aggressiveness, and several selective inhibitors of this kinase are in clinical development for various cancers, including neuroblastoma (NB). Here, we examined the sensitivity of MYCN-amplified NB cell lines to the CHK1 inhibitor PF-477736 and explored mechanisms to increase its efficacy. PF-477736 treatment of two sensitive NB cell lines, SMS-SAN and CHP134, increased the expression of two pro-apoptotic proteins, BAX and PUMA, providing a mechanism for the effect of the CHK1 inhibitor. In contrast, in NB-39-nu and SK-N-BE cell lines, PF-477736 induced DNA double-strand breaks and activated the ataxia telangiectasia mutated serine/threonine kinase (ATM)-p53-p21 axis of the DDR pathway, which rendered the cells relatively insensitive to the antiproliferative effects of the CHK1 inhibitor. Interestingly, combined treatment with PF-477736 and the ATM inhibitor Ku55933 overcame the insensitivity of NB-39-nu and SK-N-BE cells to CHK1 inhibition and induced mitotic cell death. Similarly, co-treatment with PF-477736 and NU7441, a pharmacological inhibitor of DNA-PK, which is also essential for the DDR pathway, rendered the cells sensitive to CHK1 inhibition. Taken together, our results suggest that synthetic lethality between inhibitors of CHK1 and the DDR drives G2/M checkpoint abrogation and could be a novel potential therapeutic strategy for NB. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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15 pages, 1550 KiB

Open AccessArticle

Pitavastatin Exerts Potent Anti-Inflammatory and Immunomodulatory Effects via the Suppression of AP-1 Signal Transduction in Human T Cells

by Liv Weichien Chen, Chin-Sheng Lin, Min-Chien Tsai, Shao-Fu Shih, Zhu Wei Lim, Sy-Jou Chen, Pi-Fen Tsui, Ling-Jun Ho, Jenn-Haung Lai and Jun-Ting Liou

Int. J. Mol. Sci. 2019, 20(14), 3534; https://doi.org/10.3390/ijms20143534 - 19 Jul 2019

Cited by 23 | Viewed by 5591

Abstract

Statins inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase are the standard treatment for hypercholesterolemia in atherosclerotic cardiovascular disease (ASCVD), mediated by inflammatory reactions within vessel walls. Several studies highlighted the pleiotropic effects of statins beyond their lipid-lowering properties. However, few studies investigated the effects of statins on [...] Read more.

Statins inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase are the standard treatment for hypercholesterolemia in atherosclerotic cardiovascular disease (ASCVD), mediated by inflammatory reactions within vessel walls. Several studies highlighted the pleiotropic effects of statins beyond their lipid-lowering properties. However, few studies investigated the effects of statins on T cell activation. This study evaluated the immunomodulatory capacities of three common statins, pitavastatin, atorvastatin, and rosuvastatin, in activated human T cells. The enzyme-linked immunosorbent assay (ELISA) and quantitative real time polymerase chain reaction (qRT-PCR) results demonstrated stronger inhibitory effects of pitavastatin on the cytokine production of T cells activated by phorbol 12-myristate 13-acetate (PMA) plus ionomycin, including interleukin (IL)-2, interferon (IFN)-γ, IL-6, and tumor necrosis factor α (TNF-α). Molecular investigations revealed that pitavastatin reduced both activating protein-1 (AP-1) DNA binding and transcriptional activities. Further exploration showed the selectively inhibitory effect of pitavastatin on the signaling pathways of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK). Our findings suggested that pitavastatin might provide additional benefits for treating hypercholesterolemia and ASCVD through its potent immunomodulatory effects on the suppression of ERK/p38/AP-1 signaling in human T cells. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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21 pages, 3156 KiB

Open AccessArticle

AtCRK5 Protein Kinase Exhibits a Regulatory Role in Hypocotyl Hook Development during Skotomorphogenesis

by Abu Imran Baba, Norbert Andrási, Ildikó Valkai, Teréz Gorcsa, Lilla Koczka, Zsuzsanna Darula, Katalin F. Medzihradszky, László Szabados, Attila Fehér, Gábor Rigó and Ágnes Cséplő

Int. J. Mol. Sci. 2019, 20(14), 3432; https://doi.org/10.3390/ijms20143432 - 12 Jul 2019

Cited by 21 | Viewed by 4701

Abstract

Seedling establishment following germination requires the fine tuning of plant hormone levels including that of auxin. Directional movement of auxin has a central role in the associated processes, among others, in hypocotyl hook development. Regulated auxin transport is ensured by several transporters (PINs, [...] Read more.

Seedling establishment following germination requires the fine tuning of plant hormone levels including that of auxin. Directional movement of auxin has a central role in the associated processes, among others, in hypocotyl hook development. Regulated auxin transport is ensured by several transporters (PINs, AUX1, ABCB) and their tight cooperation. Here we describe the regulatory role of the Arabidopsis thaliana CRK5 protein kinase during hypocotyl hook formation/opening influencing auxin transport and the auxin-ethylene-GA hormonal crosstalk. It was found that the Atcrk5-1 mutant exhibits an impaired hypocotyl hook establishment phenotype resulting only in limited bending in the dark. The Atcrk5-1 mutant proved to be deficient in the maintenance of local auxin accumulation at the concave side of the hypocotyl hook as demonstrated by decreased fluorescence of the auxin sensor DR5::GFP. Abundance of the polar auxin transport (PAT) proteins PIN3, PIN7, and AUX1 were also decreased in the Atcrk5-1 hypocotyl hook. The AtCRK5 protein kinase was reported to regulate PIN2 protein activity by phosphorylation during the root gravitropic response. Here it is shown that AtCRK5 can also phosphorylate in vitro the hydrophilic loops of PIN3. We propose that AtCRK5 may regulate hypocotyl hook formation in Arabidopsis thaliana through the phosphorylation of polar auxin transport (PAT) proteins, the fine tuning of auxin transport, and consequently the coordination of auxin-ethylene-GA levels. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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16 pages, 2846 KiB

Open AccessArticle

5-Amino-1-β-D-Ribofuranosyl-Imidazole-4-Carboxamide (AICAR) Reduces Peripheral Inflammation by Macrophage Phenotype Shift

by Lisa Maria Martin, Moritz Möller, Ulrike Weiss, Otto Quintus Russe, Klaus Scholich, Sandra Pierre, Gerd Geisslinger and Ellen Niederberger

Int. J. Mol. Sci. 2019, 20(13), 3255; https://doi.org/10.3390/ijms20133255 - 2 Jul 2019

Cited by 13 | Viewed by 3589

Abstract

The stimulation of the AMP-activated kinase (AMPK) by 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) has been associated with antihyperalgesia and the inhibition of nociceptive signaling in the spinal cord in models of paw inflammation. The attenuated nociception comes along with a strongly reduced paw edema, indicating that [...] Read more.

The stimulation of the AMP-activated kinase (AMPK) by 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) has been associated with antihyperalgesia and the inhibition of nociceptive signaling in the spinal cord in models of paw inflammation. The attenuated nociception comes along with a strongly reduced paw edema, indicating that peripheral antiinflammatory mechanisms contribute to antinociception. In this study, we investigated the impact of AICAR on the immune cell composition in inflamed paws, as well as the regulation of inflammatory and resolving markers in macrophages. By using fluorescence-activated cell sorting (FACS) analysis and immunofluorescence, we found a significantly increased fraction of proresolving M2 macrophages and anti-inflammatory interleukin (IL)-10 in inflamed tissue, while M1 macrophages and proinflammatory cytokines such as IL-1 were decreased by AICAR in wild type mice. In AMPKα2 knock-out mice, the M2 polarization of macrophages in the paw was missing. The results were supported by experiments in primary macrophage cultures which also showed a shift to a proresolving phenotype with decreased levels of proinflammatory mediators and increased levels of antiinflammatory mediators. However, in the cell cultures, we did not observe differences between the AMPKα2+/+ and −/− cells, thus indicating that the AICAR-induced effects are at least partially AMPK-independent. In summary, our results indicate that AICAR has potent antiinflammatory and proresolving properties in inflammation which are contributing to a reduction of inflammatory edema and antinociception. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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17 pages, 3581 KiB

Open AccessArticle

Myeloid-Specific Deletion of the AMPKα2 Subunit Alters Monocyte Protein Expression and Atherogenesis

by Beate Fisslthaler, Nina Zippel, Randa Abdel Malik, Fredy Delgado Lagos, Sven Zukunft, Janina Thoele, Daniel Siuda, Oliver Soehnlein, Ilka Wittig, Juliana Heidler, Andreas Weigert and Ingrid Fleming

Int. J. Mol. Sci. 2019, 20(12), 3005; https://doi.org/10.3390/ijms20123005 - 19 Jun 2019

Cited by 12 | Viewed by 4457

Abstract

The AMP-activated protein kinase (AMPK) is an energy sensing kinase that is activated by a drop in cellular ATP levels. Although several studies have addressed the role of the AMPKα1 subunit in monocytes and macrophages, little is known about the α2 subunit. The [...] Read more.

The AMP-activated protein kinase (AMPK) is an energy sensing kinase that is activated by a drop in cellular ATP levels. Although several studies have addressed the role of the AMPKα1 subunit in monocytes and macrophages, little is known about the α2 subunit. The aim of this study was to assess the consequences of AMPKα2 deletion on protein expression in monocytes/macrophages, as well as on atherogenesis. A proteomics approach was applied to bone marrow derived monocytes from wild-type mice versus mice specifically lacking AMPKα2 in myeloid cells (AMPKα2^∆MC mice). This revealed differentially expressed proteins, including methyltransferases. Indeed, AMPKα2 deletion in macrophages increased the ratio of S-adenosyl methionine to S-adenosyl homocysteine and increased global DNA cytosine methylation. Also, methylation of the vascular endothelial growth factor and matrix metalloproteinase-9 (MMP9) genes was increased in macrophages from AMPKα2^∆MC mice, and correlated with their decreased expression. To link these findings with an in vivo phenotype, AMPKα2^∆MC mice were crossed onto the ApoE^-/- background and fed a western diet. ApoExAMPKα2^∆MC mice developed smaller atherosclerotic plaques than their ApoExα2^fl/fl littermates, that contained fewer macrophages and less MMP9 than plaques from ApoExα2^fl/fl littermates. These results indicate that the AMPKα2 subunit in myeloid cells influences DNA methylation and thus protein expression and contributes to the development of atherosclerotic plaques. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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15 pages, 1927 KiB

Open AccessArticle

Analysis of the TP53 Deleterious Single Nucleotide Polymorphisms Impact on Estrogen Receptor Alpha-p53 Interaction: A Machine Learning Approach

by Kumaraswamy Naidu Chitrala, Mitzi Nagarkatti, Prakash Nagarkatti and Suneetha Yeguvapalli

Int. J. Mol. Sci. 2019, 20(12), 2962; https://doi.org/10.3390/ijms20122962 - 18 Jun 2019

Cited by 9 | Viewed by 3706

Abstract

Breast cancer is a leading cancer type and one of the major health issues faced by women around the world. Some of its major risk factors include body mass index, hormone replacement therapy, family history and germline mutations. Of these risk factors, estrogen [...] Read more.

Breast cancer is a leading cancer type and one of the major health issues faced by women around the world. Some of its major risk factors include body mass index, hormone replacement therapy, family history and germline mutations. Of these risk factors, estrogen levels play a crucial role. Among the estrogen receptors, estrogen receptor alpha (ERα) is known to interact with tumor suppressor protein p53 directly thereby repressing its function. Previously, we have studied the impact of deleterious breast cancer-associated non-synonymous single nucleotide polymorphisms (nsnps) rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 gene on the p53 DNA-binding core domain. In the present study, we aimed to analyze the impact of these mutations on p53–ERα interaction. To this end, we, have modelled the full-length structure of human p53 and validated its quality using PROCHECK and subjected it to energy minimization using NOMAD-Ref web server. Three-dimensional structure of ERα activation function-2 (AF-2) domain was downloaded from the protein data bank. Interactions between the modelled native and mutant (R110P, P278A, P151T) p53 with ERα was studied using ZDOCK. Machine learning predictions on the interactions were performed using Weka software. Results from the protein–protein docking showed that the atoms, residues and solvent accessibility surface area (SASA) at the interface was increased in both p53 and ERα for R110P mutation compared to the native complexes indicating that the mutation R110P has more impact on the p53–ERα interaction compared to the other two mutants. Mutations P151T and P278A, on the other hand, showed a large deviation from the native p53-ERα complex in atoms and residues at the surface. Further, results from artificial neural network analysis showed that these structural features are important for predicting the impact of these three mutations on p53–ERα interaction. Overall, these three mutations showed a large deviation in total SASA in both p53 and ERα. In conclusion, results from our study will be crucial in making the decisions for hormone-based therapies against breast cancer. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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17 pages, 10454 KiB

Open AccessArticle

Src and ROCK Kinases Differentially Regulate Mineralization of Human Osteosarcoma Saos-2 Cells

by Agnieszka Strzelecka-Kiliszek, Marta Romiszewska, Lukasz Bozycki, Saida Mebarek, Joanna Bandorowicz-Pikula, Rene Buchet and Slawomir Pikula

Int. J. Mol. Sci. 2019, 20(12), 2872; https://doi.org/10.3390/ijms20122872 - 12 Jun 2019

Cited by 7 | Viewed by 4230

Abstract

Osteoblasts initiate bone mineralization by releasing matrix vesicles (MVs) into the extracellular matrix (ECM). MVs promote the nucleation process of apatite formation from Ca²⁺ and P_i in their lumen and bud from the microvilli of osteoblasts during bone development. Tissue non-specific [...] Read more.

Osteoblasts initiate bone mineralization by releasing matrix vesicles (MVs) into the extracellular matrix (ECM). MVs promote the nucleation process of apatite formation from Ca²⁺ and P_i in their lumen and bud from the microvilli of osteoblasts during bone development. Tissue non-specific alkaline phosphatase (TNAP) as well as annexins (among them, AnxA6) are abundant proteins in MVs that are engaged in mineralization. In addition, sarcoma proto-oncogene tyrosine-protein (Src) kinase and Rho-associated coiled-coil (ROCK) kinases, which are involved in vesicular transport, may also regulate the mineralization process. Upon stimulation in osteogenic medium containing 50 μg/mL of ascorbic acid (AA) and 7.5 mM of β-glycerophosphate (β-GP), human osteosarcoma Saos-2 cells initiated mineralization, as evidenced by Alizarin Red-S (AR-S) staining, TNAP activity, and the partial translocation of AnxA6 from cytoplasm to the plasma membrane. The addition of 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d] pyrimidine (PP2), which is an inhibitor of Src kinase, significantly inhibited the mineralization process when evaluated by the above criteria. In contrast, the addition of (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide hydrochloride (Y-27632), which is an inhibitor of ROCK kinase, did not affect significantly the mineralization induced in stimulated Saos-2 cells as denoted by AR-S and TNAP activity. In conclusion, mineralization by human osteosarcoma Saos-2 cells seems to be differently regulated by Src and ROCK kinases. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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12 pages, 961 KiB

Open AccessArticle

AMPK Alters Detrusor Contractility During Emptying in Normal Bladder and Hypertrophied Bladder with Partial Bladder Outlet Obstruction via CaMKKβ

by Bo-Hwa Choi, Long-Hu Jin, Doo Yong Chung, Tae Jin Cho, Ju-Hee Kang, Tack Lee and Chang-Shin Park

Int. J. Mol. Sci. 2019, 20(11), 2650; https://doi.org/10.3390/ijms20112650 - 29 May 2019

Cited by 6 | Viewed by 2737

Abstract

AMP-activated protein kinase (AMPK) has been implicated in contractility changes in bladders with partial bladder outlet obstruction (PBOO), but the role of AMPK in the contractile response of normal bladder remains unclear. We investigated the phosphorylation of AMPKα and expression of the involved [...] Read more.

AMP-activated protein kinase (AMPK) has been implicated in contractility changes in bladders with partial bladder outlet obstruction (PBOO), but the role of AMPK in the contractile response of normal bladder remains unclear. We investigated the phosphorylation of AMPKα and expression of the involved upstream AMPK kinases (AMPKKs) in a model of bladders with PBOO and sought to determine whether the pharmacological inhibition of these two factors affected detrusor contractility in normal bladders, using female Sprague–Dawley rats. Cystometry and Western blot analysis were performed in rats that were subjected to PBOO induction or a sham operation. Cystometry was performed in normal rats that received selective inhibitors of AMPKα and Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKKβ) (compound C and STO-609, respectively) at doses determined in the experiments. In the PBOO bladders, bladder weight and micturition pressure (MP) were higher and AMPKα phosphorylation (T172) and CaMKKβ expression was significantly reduced. Compound C and STO-609 increased MP. The increased contractile response in bladders with PBOO-induced hypertrophy was related to decreased CaMKKβ/AMPK signaling activity, and the pharmacological inhibition of this pathway in normal bladders increased detrusor contractility, implying a role of CaMKKβ/AMPK signaling in the bladder in the regulation of detrusor contractility. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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27 pages, 9381 KiB

Open AccessArticle

Experiments with Snails Add to Our Knowledge about the Role of aPKC Subfamily Kinases in Learning

by Ekaterina Chesnokova, Alena Zuzina, Natalia Bal, Aliya Vinarskaya, Matvey Roshchin, Alexander Artyuhov, Erdem Dashinimaev, Nikolay Aseyev, Pavel Balaban and Peter Kolosov

Int. J. Mol. Sci. 2019, 20(9), 2117; https://doi.org/10.3390/ijms20092117 - 29 Apr 2019

Cited by 2 | Viewed by 4010

Abstract

Protein kinase Mζ is considered important for memory formation and maintenance in different species, including invertebrates. PKMζ participates in multiple molecular pathways in neurons, regulating translation initiation rate, AMPA receptors turnover, synaptic scaffolding assembly, and other processes. Here, for the first time, we [...] Read more.

Protein kinase Mζ is considered important for memory formation and maintenance in different species, including invertebrates. PKMζ participates in multiple molecular pathways in neurons, regulating translation initiation rate, AMPA receptors turnover, synaptic scaffolding assembly, and other processes. Here, for the first time, we established the sequence of mRNA encoding PKMζ homolog in land snail Helix lucorum. We annotated important features of this mRNA: domains, putative capping sites, translation starts, and splicing sites. We discovered that this mRNA has at least two isoforms, and one of them lacks sequence encoding C1 domain. C1 deletion may be unique for snail because it has not been previously found in other species. We performed behavioral experiments with snails, measured expression levels of identified isoforms, and confirmed that their expression correlates with one type of learning. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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22 pages, 2622 KiB

Open AccessArticle

Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer

by Amreena Suri, Anders W. Bailey, Maurício T. Tavares, Hendra Gunosewoyo, Connor P. Dyer, Alex T. Grupenmacher, David R. Piper, Robert A. Horton, Tadanori Tomita, Alan P. Kozikowski, Saktimayee M. Roy and Simone T. Sredni

Int. J. Mol. Sci. 2019, 20(9), 2112; https://doi.org/10.3390/ijms20092112 - 29 Apr 2019

Cited by 32 | Viewed by 8536

Abstract

Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal [...] Read more.

Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). Our analyses demonstrated that: (1) CFI-400437 had the greatest impact overall, but similar to CFI-400945, it is not optimal for brain exposure. Also, their phenotypic anti-cancer impact may, in part, be a consequence of the inhibition of Aurora kinases (AURKs). (2) Centrinone and centrinone B are the most selective PLK4 inhibitors but they are the least likely to penetrate the brain. (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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17 pages, 9308 KiB

Open AccessArticle

Drosophila Homeodomain-Interacting Protein Kinase (Hipk) Phosphorylates the Homeodomain Proteins Homeobrain, Empty Spiracles, and Muscle Segment Homeobox

by Eva Louise Steinmetz, Denise Nicole Dewald, Nadine Luxem and Uwe Walldorf

Int. J. Mol. Sci. 2019, 20(8), 1931; https://doi.org/10.3390/ijms20081931 - 19 Apr 2019

Viewed by 3020

Abstract

The Drosophila homeodomain-interacting protein kinase (Hipk) is the fly representative of the well-conserved group of HIPKs in vertebrates. It was initially found through its characteristic interactions with homeodomain proteins. Hipk is involved in a variety of important developmental processes, such as the development [...] Read more.

The Drosophila homeodomain-interacting protein kinase (Hipk) is the fly representative of the well-conserved group of HIPKs in vertebrates. It was initially found through its characteristic interactions with homeodomain proteins. Hipk is involved in a variety of important developmental processes, such as the development of the eye or the nervous system. In the present study, we set Hipk and the Drosophila homeodomain proteins Homeobrain (Hbn), Empty spiracles (Ems), and Muscle segment homeobox (Msh) in an enzyme-substrate relationship. These homeoproteins are transcription factors that function during Drosophila neurogenesis and are, at least in part, conserved in vertebrates. We reveal a physical interaction between Hipk and the three homeodomain proteins in vivo using bimolecular fluorescence complementation (BiFC). In the course of in vitro phosphorylation analysis and subsequent mutational analysis we mapped several Hipk phosphorylation sites of Hbn, Ems, and Msh. The phosphorylation of Hbn, Ems, and Msh may provide further insight into the function of Hipk during development of the Drosophila nervous system. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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14 pages, 4088 KiB

Open AccessArticle

The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis

by Jung-Min Kim, Yeon-Suk Yang, Kwang Hwan Park, Hwanhee Oh, Matthew B. Greenblatt and Jae-Hyuck Shim

Int. J. Mol. Sci. 2019, 20(8), 1803; https://doi.org/10.3390/ijms20081803 - 12 Apr 2019

Cited by 106 | Viewed by 5934

Abstract

Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal [...] Read more.

Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1^OsxMek2^−/−), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function. Additionally, tamoxifen-induced deletion of Mek1 and Mek2 in osteoprogenitors in adult mice (Mek1^Osx-ERTMek2^−/−) significantly reduced bone mass. Mechanistically, this corresponded to decreased activation of osteoblast master regulators, including RUNX2, ATF4, and β-catenin. Finally, we identified potential regulators of osteoblast differentiation in the ERK MAPK pathway using unbiased phospho-mass spectrometry. These observations demonstrate essential roles of ERK activation in osteogenesis and bone formation. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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8 pages, 731 KiB

Open AccessCommunication

Autophosphorylation of Orphan Receptor ERBB2 Can Be Induced by Extracellular Treatment with Mildly Alkaline Media

by Oxana V. Serova, Natalia A. Chachina, Elena A. Gantsova, Nadezhda V. Popova, Alexander G. Petrenko and Igor E. Deyev

Int. J. Mol. Sci. 2019, 20(6), 1515; https://doi.org/10.3390/ijms20061515 - 26 Mar 2019

Cited by 10 | Viewed by 3558

Abstract

ErbB2 is an oncogene receptor tyrosine kinase linked to breast cancer. It is a member of the epidermal growth factor receptor (EGFR) minifamily. ErbB2 is currently viewed as an orphan receptor since, by itself, it does not bind EGF-like ligands and can be [...] Read more.

ErbB2 is an oncogene receptor tyrosine kinase linked to breast cancer. It is a member of the epidermal growth factor receptor (EGFR) minifamily. ErbB2 is currently viewed as an orphan receptor since, by itself, it does not bind EGF-like ligands and can be activated only when overexpressed in malignant cells or complexed with ErbB3, another member of the EGFR minifamily. Here, we report that ErbB2 can be activated by extracellular application of mildly alkaline (pH 8–9) media to ErbB2-transfected cells. We also show that the activation of the ErbB2 receptor by alkali is dose-dependent and buffer-independent. The endogenous ErbB2 receptor of A431 cell line can also undergo alkali-dependent autophosphorylation. Thus, we describe a novel ligand-independent mechanism of ErbB2 receptor activation. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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13 pages, 2866 KiB

Open AccessArticle

Mechanisms of FSH- and Amphiregulin-Induced MAP Kinase 3/1 Activation in Pig Cumulus-Oocyte Complexes During Maturation In Vitro

by Radek Prochazka and Lucie Nemcova

Int. J. Mol. Sci. 2019, 20(5), 1179; https://doi.org/10.3390/ijms20051179 - 7 Mar 2019

Cited by 11 | Viewed by 4695

Abstract

The maturation of mammalian oocytes in vitro can be stimulated by gonadotropins (follicle-stimulating hormone, FSH) or their intrafollicular mediator, epidermal growth factor (EGF)-like peptide—amphiregulin (AREG). We have shown previously that in pig cumulus-oocyte complexes (COCs), FSH induces expression and the synthesis of AREG [...] Read more.

The maturation of mammalian oocytes in vitro can be stimulated by gonadotropins (follicle-stimulating hormone, FSH) or their intrafollicular mediator, epidermal growth factor (EGF)-like peptide—amphiregulin (AREG). We have shown previously that in pig cumulus-oocyte complexes (COCs), FSH induces expression and the synthesis of AREG that binds to EGF receptor (EGFR) and activates the mitogen-activated protein kinase 3/1 (MAPK3/1) signaling pathway. However, in this study we found that FSH also caused a rapid activation of MAPK3/1 in the cumulus cells, which cannot be explained by the de novo synthesis of AREG. The rapid MAPK3/1 activation required EGFR tyrosine kinase (TK) activity, was sensitive to SRC proto-oncogene non-receptor tyrosine kinase (SRC)-family and protein kinase C (PKC) inhibitors, and was resistant to inhibitors of protein kinase A (PKA) and metalloproteinases. AREG also induced the rapid activation of MAPK3/1 in cumulus cells, but this activation was only dependent on the EGFR TK activity. We conclude that in cumulus cells, FSH induces a rapid activation of MAPK3/1 by the ligand-independent transactivation of EGFR, requiring SRC and PKC activities. This rapid activation of MAPK3/1 precedes the second mechanism participating in the generation and maintenance of active MAPK3/1—the ligand-dependent activation of EGFR depending on the synthesis of EGF-like peptides. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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15 pages, 1612 KiB

Open AccessArticle

An Anabolic Signaling Response of Rat Soleus Muscle to Eccentric Contractions Following Hindlimb Unloading: A Potential Role of Stretch-Activated Ion Channels

by Sergey Tyganov, Timur Mirzoev and Boris Shenkman

Int. J. Mol. Sci. 2019, 20(5), 1165; https://doi.org/10.3390/ijms20051165 - 7 Mar 2019

Cited by 23 | Viewed by 3988

Abstract

Mechanisms that convert a mechanical signal into a biochemical response in an atrophied skeletal muscle remain poorly understood. The aims of the study were to evaluate a temporal response of anabolic signaling and protein synthesis (PS) to eccentric contractions (EC) in rat soleus [...] Read more.

Mechanisms that convert a mechanical signal into a biochemical response in an atrophied skeletal muscle remain poorly understood. The aims of the study were to evaluate a temporal response of anabolic signaling and protein synthesis (PS) to eccentric contractions (EC) in rat soleus during hindlimb unloading (HU); and to assess a possible role of stretch-activated ion channels (SAC) in the propagation of a mechanical signal to mTORC1 following HU. Following HU, an isolated soleus was subjected to EC. Upon completion of EC, muscles were collected for western blot analyses to determine the content/phosphorylation of the key anabolic markers. We found that a degree of EC-induced p70S6K phosphorylation and the rate of PS in the soleus of 3- and 7-day unloaded rats was significantly less than that in control. A decrease in EC-induced phosphorylation of p70S6K, RPS6 and PS in the 7-day unloaded soleus treated with SAC inhibitor did not differ from that of the 7-day unloaded soleus without SAC blockade. The results of the study suggest that (i) HU results in a blunted anabolic response to a bout of EC, (ii) attenuation of mTORC1-signaling and PS in response to EC in unloaded soleus may be associated with inactivation of SAC. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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Review

Jump to: Research

16 pages, 757 KiB

Open AccessReview

Neuroprotective Properties of Linagliptin: Focus on Biochemical Mechanisms in Cerebral Ischemia, Vascular Dysfunction and Certain Neurodegenerative Diseases

by Michał Wiciński, Karol Górski, Maciej Walczak, Eryk Wódkiewicz, Maciej Słupski, Katarzyna Pawlak-Osińska and Bartosz Malinowski

Int. J. Mol. Sci. 2019, 20(16), 4052; https://doi.org/10.3390/ijms20164052 - 20 Aug 2019

Cited by 21 | Viewed by 5170

Abstract

Linagliptin is a representative of dipeptidyl peptidase 4 (DPP-4) inhibitors which are registered and used effectively in a treatment of diabetes mellitus type 2. They increase the levels of active forms of endogenous incretins such as GLP-1 and GIP by inhibiting their enzymatic [...] Read more.

Linagliptin is a representative of dipeptidyl peptidase 4 (DPP-4) inhibitors which are registered and used effectively in a treatment of diabetes mellitus type 2. They increase the levels of active forms of endogenous incretins such as GLP-1 and GIP by inhibiting their enzymatic decomposition. Scientific reports suggest beneficial effects of linagliptin administration via immunological and biochemical pathways involved in neuroprotective processes of CNS. Linagliptin’s administration leads to a decrease in the concentration of proinflammatory factors such as: TNF-α, IL-6 and increases the number of anti-inflammatory patrolling monocytes CX3CR1^bright. Significant reduction in Aβ42 level has been associated with the use of linagliptin implying potential application in Alzheimer’s disease. Linagliptin improved vascular functions by increasing production of nitric oxide (NO) and limiting concentration of apolipoprotein B. Linagliptin-induced decrease in macrophages infiltration may provide improvement in atheromatous plaque stabilization. Premedication with linagliptin increases neuron’s survival after stroke and augments neuronal stem cells proliferation. It seems to be connected with SDF-1α/CXCR4 signaling pathway. Linagliptin prevented abnormal proliferation and migration of rat brain microvascular endothelial cells in a state of hypoperfusion via SIRT1/HIF-1α/VEGF pathway. The article presents a summary of the studies assessing neuroprotective properties of linagliptin with special emphasis on cerebral ischemia, vascular dysfunction and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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18 pages, 821 KiB

Open AccessReview

Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy

by Ursula Bommhardt, Burkhart Schraven and Luca Simeoni

Int. J. Mol. Sci. 2019, 20(14), 3500; https://doi.org/10.3390/ijms20143500 - 16 Jul 2019

Cited by 92 | Viewed by 12774

Abstract

In recent years, the lymphocyte-specific protein tyrosine kinase (Lck) has emerged as one of the key molecules regulating T-cell functions. Studies using Lck knock-out mice or Lck-deficient T-cell lines have shown that Lck regulates the initiation of TCR signaling, T-cell development, and T-cell [...] Read more.

In recent years, the lymphocyte-specific protein tyrosine kinase (Lck) has emerged as one of the key molecules regulating T-cell functions. Studies using Lck knock-out mice or Lck-deficient T-cell lines have shown that Lck regulates the initiation of TCR signaling, T-cell development, and T-cell homeostasis. Because of the crucial role of Lck in T-cell responses, strategies have been employed to redirect Lck activity to improve the efficacy of chimeric antigen receptors (CARs) and to potentiate T-cell responses in cancer immunotherapy. In addition to the well-studied role of Lck in T cells, evidence has been accumulated suggesting that Lck is also expressed in the brain and in tumor cells, where it actively takes part in signaling processes regulating cellular functions like proliferation, survival and memory. Therefore, Lck has emerged as a novel druggable target molecule for the treatment of cancer and neuronal diseases. In this review, we will focus on these new functions of Lck. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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15 pages, 916 KiB

Open AccessReview

Plant Phytochromes and their Phosphorylation

by Quyen T. N. Hoang, Yun-Jeong Han and Jeong-Il Kim

Int. J. Mol. Sci. 2019, 20(14), 3450; https://doi.org/10.3390/ijms20143450 - 13 Jul 2019

Cited by 30 | Viewed by 9606

Abstract

Extensive research over several decades in plant light signaling mediated by photoreceptors has identified the molecular mechanisms for how phytochromes regulate photomorphogenic development, which includes degradation of phytochrome-interacting factors (PIFs) and inactivation of COP1-SPA complexes with the accumulation of master transcription factors for [...] Read more.

Extensive research over several decades in plant light signaling mediated by photoreceptors has identified the molecular mechanisms for how phytochromes regulate photomorphogenic development, which includes degradation of phytochrome-interacting factors (PIFs) and inactivation of COP1-SPA complexes with the accumulation of master transcription factors for photomorphogenesis, such as HY5. However, the initial biochemical mechanism for the function of phytochromes has not been fully elucidated. Plant phytochromes have long been known as phosphoproteins, and a few protein phosphatases that directly interact with and dephosphorylate phytochromes have been identified. However, there is no report thus far of a protein kinase that acts on phytochromes. On the other hand, plant phytochromes have been suggested as autophosphorylating serine/threonine protein kinases, proposing that the kinase activity might be important for their functions. Indeed, the autophosphorylation of phytochromes has been reported to play an important role in the regulation of plant light signaling. More recently, evidence that phytochromes function as protein kinases in plant light signaling has been provided using phytochrome mutants displaying reduced kinase activities. In this review, we highlight recent advances in the reversible phosphorylation of phytochromes and their functions as protein kinases in plant light signaling. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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19 pages, 1053 KiB

Open AccessReview

Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

by Nami Kim, Dongmei Chen, Xiao Zhen Zhou and Tae Ho Lee

Int. J. Mol. Sci. 2019, 20(13), 3131; https://doi.org/10.3390/ijms20133131 - 26 Jun 2019

Cited by 61 | Viewed by 6863

Abstract

Regulated neuronal cell death plays an essential role in biological processes in normal physiology, including the development of the nervous system. However, the deregulation of neuronal apoptosis by various factors leads to neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease (AD). Death-associated [...] Read more.

Regulated neuronal cell death plays an essential role in biological processes in normal physiology, including the development of the nervous system. However, the deregulation of neuronal apoptosis by various factors leads to neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease (AD). Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca²⁺/CaM)-dependent serine/threonine (Ser/Thr) protein kinase that activates death signaling and regulates apoptotic neuronal cell death. Although DAPK1 is tightly regulated under physiological conditions, DAPK1 deregulation in the brain contributes to the development of neurological disorders. In this review, we describe the molecular mechanisms of DAPK1 regulation in neurons under various stresses. We also discuss the role of DAPK1 signaling in the phosphorylation-dependent and phosphorylation-independent regulation of its downstream targets in neuronal cell death. Moreover, we focus on the major impact of DAPK1 deregulation on the progression of neurodegenerative diseases and the development of drugs targeting DAPK1 for the treatment of diseases. Therefore, this review summarizes the DAPK1 phosphorylation signaling pathways in various neurodegenerative diseases. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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22 pages, 1181 KiB

Open AccessReview

Targeting Protein Kinases to Enhance the Response to anti-PD-1/PD-L1 Immunotherapy

by Marilina García-Aranda and Maximino Redondo

Int. J. Mol. Sci. 2019, 20(9), 2296; https://doi.org/10.3390/ijms20092296 - 9 May 2019

Cited by 35 | Viewed by 6154

Abstract

The interaction between programmed cell death protein (PD-1) and its ligand (PD-L1) is one of the main pathways used by some tumors to escape the immune response. In recent years, immunotherapies based on the use of antibodies against PD-1/PD-L1 have been postulated as [...] Read more.

The interaction between programmed cell death protein (PD-1) and its ligand (PD-L1) is one of the main pathways used by some tumors to escape the immune response. In recent years, immunotherapies based on the use of antibodies against PD-1/PD-L1 have been postulated as a great promise for cancer treatment, increasing total survival compared to standard therapy in different tumors. Despite the hopefulness of these results, a significant percentage of patients do not respond to such therapy or will end up evolving toward a progressive disease. Besides their role in PD-L1 expression, altered protein kinases in tumor cells can limit the effectiveness of PD-1/PD-L1 blocking therapies at different levels. In this review, we describe the role of kinases that appear most frequently altered in tumor cells and that can be an impediment for the success of immunotherapies as well as the potential utility of protein kinase inhibitors to enhance the response to such treatments. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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18 pages, 743 KiB

Open AccessReview

Precision Revisited: Targeting Microcephaly Kinases in Brain Tumors

by Gianmarco Pallavicini, Gaia E. Berto and Ferdinando Di Cunto

Int. J. Mol. Sci. 2019, 20(9), 2098; https://doi.org/10.3390/ijms20092098 - 28 Apr 2019

Cited by 10 | Viewed by 4476

Abstract

Glioblastoma multiforme and medulloblastoma are the most frequent high-grade brain tumors in adults and children, respectively. Standard therapies for these cancers are mainly based on surgical resection, radiotherapy, and chemotherapy. However, intrinsic or acquired resistance to treatment occurs almost invariably in the first [...] Read more.

Glioblastoma multiforme and medulloblastoma are the most frequent high-grade brain tumors in adults and children, respectively. Standard therapies for these cancers are mainly based on surgical resection, radiotherapy, and chemotherapy. However, intrinsic or acquired resistance to treatment occurs almost invariably in the first case, and side effects are unacceptable in the second. Therefore, the development of new, effective drugs is a very important unmet medical need. A critical requirement for developing such agents is to identify druggable targets required for the proliferation or survival of tumor cells, but not of other cell types. Under this perspective, genes mutated in congenital microcephaly represent interesting candidates. Congenital microcephaly comprises a heterogeneous group of disorders in which brain volume is reduced, in the absence or presence of variable syndromic features. Genetic studies have clarified that most microcephaly genes encode ubiquitous proteins involved in mitosis and in maintenance of genomic stability, but the effects of their inactivation are particularly strong in neural progenitors. It is therefore conceivable that the inhibition of the function of these genes may specifically affect the proliferation and survival of brain tumor cells. Microcephaly genes encode for a few kinases, including CITK, PLK4, AKT3, DYRK1A, and TRIO. In this review, we summarize the evidence indicating that the inhibition of these molecules could exert beneficial effects on different aspects of brain cancer treatment. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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24 pages, 740 KiB

Open AccessReview

Targeting Tyrosine kinases in Renal Cell Carcinoma: “New Bullets against Old Guys”

by Teresa Alonso-Gordoa, María Laura García-Bermejo, Enrique Grande, Pilar Garrido, Alfredo Carrato and Javier Molina-Cerrillo

Int. J. Mol. Sci. 2019, 20(8), 1901; https://doi.org/10.3390/ijms20081901 - 17 Apr 2019

Cited by 40 | Viewed by 4661

Abstract

Clear cell renal cell carcinoma (ccRCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5% of cancer deaths. The molecular biology underlying renal cell carcinoma (RCC) development and progression has been a key milestone in the management [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5% of cancer deaths. The molecular biology underlying renal cell carcinoma (RCC) development and progression has been a key milestone in the management of this type of tumor. The discovery of Von Hippel Lindau (VHL) gene alterations that arouse in 50% of ccRCC patients, leads the identification of an intracellular accumulation of HIF and, consequently an increase of VEGFR expression. This change in cell biology represents a new paradigm in the treatment of metastatic renal cancer by targeting angiogenesis. Currently, there are multiple therapeutic drugs available for advanced disease, including therapies against VEGFR with successful results in patients´ survival. Other tyrosine kinases’ pathways, including PDGFR, Axl or MET have emerged as key signaling pathways involved in RCC biology. Indeed, promising new drugs targeting those tyrosine kinases have exhibited outstanding efficacy. In this review we aim to present an overview of the central role of these tyrosine kinases’ activities in relevant biological processes for kidney cancer and their usefulness in RCC targeted therapy development. In the immunotherapy era, angiogenesis is still an “old guy” that the medical community is trying to fight using “new bullets”. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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14 pages, 594 KiB

Open AccessReview

Thrombomodulin Regulation of Mitogen-Activated Protein Kinases

by Hemant Giri, Xiaofeng Cai, Sumith R. Panicker, Indranil Biswas and Alireza R. Rezaie

Int. J. Mol. Sci. 2019, 20(8), 1851; https://doi.org/10.3390/ijms20081851 - 15 Apr 2019

Cited by 14 | Viewed by 6217

Abstract

The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection, cardiovascular disease, and cancer has been well established. Recently, coagulation factors have also emerged as key players in regulating intracellular signaling pathways during inflammation. [...] Read more.

The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection, cardiovascular disease, and cancer has been well established. Recently, coagulation factors have also emerged as key players in regulating intracellular signaling pathways during inflammation. Among coagulation factors, thrombomodulin, as a high affinity receptor for thrombin on vascular endothelial cells, has been discovered to be a potent anti-inflammatory and anti-tumorigenic signaling molecule. The protective signaling function of thrombomodulin is separate from its well-recognized role in the clotting cascade, which is to function as an anti-coagulant receptor in order to switch the specificity of thrombin from a procoagulant to an anti-coagulant protease. The underlying protective signaling mechanism of thrombomodulin remains largely unknown, though a few published reports link the receptor to the regulation of MAPKs under different (patho)physiological conditions. The goal of this review is to summarize what is known about the regulatory relationship between thrombomodulin and MAPKs. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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30 pages, 2227 KiB

Open AccessReview

Two Component Regulatory Systems and Antibiotic Resistance in Gram-Negative Pathogens

by Anjali Y. Bhagirath, Yanqi Li, Rakesh Patidar, Katherine Yerex, Xiaoxue Ma, Ayush Kumar and Kangmin Duan

Int. J. Mol. Sci. 2019, 20(7), 1781; https://doi.org/10.3390/ijms20071781 - 10 Apr 2019

Cited by 99 | Viewed by 12280

Abstract

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant [...] Read more.

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant number of two-component systems (TCSs) exist in these pathogens, which are involved in regulation of gene expression in response to environmental signals such as antibiotic exposure. While the development of antimicrobial resistance is a complex phenomenon, it has been shown that TCSs are involved in sensing antibiotics and regulating genes associated with antibiotic resistance. In this review, we aim to interpret current knowledge about the signaling mechanisms of TCSs in these three pathogenic bacteria. We further attempt to answer questions about the role of TCSs in antimicrobial resistance. We will also briefly discuss how specific two-component systems present in K. pneumoniae, A. baumannii, and P. aeruginosa may serve as potential therapeutic targets. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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12 pages, 558 KiB

Open AccessReview

The Cardioprotective Signaling Activity of Activated Protein C in Heart Failure and Ischemic Heart Diseases

by Di Ren, Hemant Giri, Ji Li and Alireza R. Rezaie

Int. J. Mol. Sci. 2019, 20(7), 1762; https://doi.org/10.3390/ijms20071762 - 10 Apr 2019

Cited by 18 | Viewed by 5459

Abstract

Activated protein C (APC) is a vitamin-K dependent plasma serine protease, which functions as a natural anticoagulant to downregulate thrombin generation in the clotting cascade. APC also modulates cellular homeostasis by exhibiting potent cytoprotective and anti-inflammatory signaling activities. The beneficial cytoprotective effects of [...] Read more.

Activated protein C (APC) is a vitamin-K dependent plasma serine protease, which functions as a natural anticoagulant to downregulate thrombin generation in the clotting cascade. APC also modulates cellular homeostasis by exhibiting potent cytoprotective and anti-inflammatory signaling activities. The beneficial cytoprotective effects of APC have been extensively studied and confirmed in a number of preclinical disease and injury models including sepsis, type-1 diabetes and various ischemia/reperfusion diseases. It is now well-known that APC modulates downstream cell signaling networks and transcriptome profiles when it binds to the endothelial protein C receptor (EPCR) to activate protease-activated receptor 1 (PAR1) on various cell types. However, despite much progress, details of the downstream signaling mechanism of APC and its crosstalk with other signaling networks are far from being fully understood. In this review, we focus on the cardioprotective properties of APC in ischemic heart disease and heart failure with a special emphasis on recent discoveries related to the modulatory effect of APC on AMP-activated protein kinase (AMPK), PI3K/AKT, and mTORC1 signaling pathways. The cytoprotective properties of APC might provide a novel strategy for future therapies in cardiac diseases. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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16 pages, 1893 KiB

Open AccessReview

Serine/Threonine Protein Kinase STK16

by Junjun Wang, Xinmiao Ji, Juanjuan Liu and Xin Zhang

Int. J. Mol. Sci. 2019, 20(7), 1760; https://doi.org/10.3390/ijms20071760 - 10 Apr 2019

Cited by 14 | Viewed by 5160

Abstract

STK16 (Ser/Thr kinase 16, also known as Krct/PKL12/MPSK1/TSF-1) is a myristoylated and palmitoylated Ser/Thr protein kinase that is ubiquitously expressed and conserved among all eukaryotes. STK16 is distantly related to the other kinases and belongs to the NAK kinase family that has an [...] Read more.

STK16 (Ser/Thr kinase 16, also known as Krct/PKL12/MPSK1/TSF-1) is a myristoylated and palmitoylated Ser/Thr protein kinase that is ubiquitously expressed and conserved among all eukaryotes. STK16 is distantly related to the other kinases and belongs to the NAK kinase family that has an atypical activation loop architecture. As a membrane-associated protein that is primarily localized to the Golgi, STK16 has been shown to participate in the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. This review aims to provide a comprehensive summary of the progress made in recent research about STK16, ranging from its distribution, molecular characterization, post-translational modification (fatty acylation and phosphorylation), interactors (GlcNAcK/DRG1/MAL2/Actin/WDR1), and related functions. As a relatively underexplored kinase, more studies are encouraged to unravel its regulation mechanisms and cellular functions. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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16 pages, 900 KiB

Open AccessReview

Liraglutide and its Neuroprotective Properties—Focus on Possible Biochemical Mechanisms in Alzheimer’s Disease and Cerebral Ischemic Events

by Michał Wiciński, Maciej Socha, Bartosz Malinowski, Eryk Wódkiewicz, Maciej Walczak, Karol Górski, Maciej Słupski and Katarzyna Pawlak-Osińska

Int. J. Mol. Sci. 2019, 20(5), 1050; https://doi.org/10.3390/ijms20051050 - 28 Feb 2019

Cited by 61 | Viewed by 8526

Abstract

Liraglutide is a GLP-1 analog (glucagon like peptide-1) used primarily in the treatment of diabetes mellitus type 2 (DM2) and obesity. The literature starts to suggest that liraglutide may reduce the effects of ischemic stroke by activating anti-apoptotic pathways, as well as limiting [...] Read more.

Liraglutide is a GLP-1 analog (glucagon like peptide-1) used primarily in the treatment of diabetes mellitus type 2 (DM2) and obesity. The literature starts to suggest that liraglutide may reduce the effects of ischemic stroke by activating anti-apoptotic pathways, as well as limiting the harmful effects of free radicals. The GLP-1R expression has been reported in the cerebral cortex, especially occipital and frontal lobes, the hypothalamus, and the thalamus. Liraglutide reduced the area of ischemia caused by MCAO (middle cerebral artery occlusion), limited neurological deficits, decreased hyperglycemia caused by stress, and presented anti-apoptotic effects by increasing the expression of Bcl-2 and Bcl-xl proteins and reduction of Bax and Bad protein expression. The pharmaceutical managed to decrease concentrations of proapoptotic factors, such as NF-κB (Nuclear Factor-kappa β), ICAM-1 (Intercellular Adhesion Molecule 1), caspase-3, and reduced the level of TUNEL-positive cells. Liraglutide was able to reduce the level of free radicals by decreasing the level of malondialdehyde (MDA), and increasing the superoxide dismutase level (SOD), glutathione (GSH), and catalase. Liraglutide may affect the neurovascular unit causing its remodeling, which seems to be crucial for recovery after stroke. Liraglutide may stabilize atherosclerotic plaque, as well as counteract its early formation and further development. Liraglutide, through its binding to GLP-1R (glucagon like peptide-1 receptor) and consequent activation of PI3K/MAPK (Phosphoinositide 3-kinase/mitogen associated protein kinase) dependent pathways, may have a positive impact on Aβ (amyloid beta) trafficking and clearance by increasing the presence of Aβ transporters in cerebrospinal fluid. Liraglutide seems to affect tau pathology. It is possible that liraglutide may have some stem cell stimulating properties. The effects may be connected with PKA (phosphorylase kinase A) activation. This paper presents potential mechanisms of liraglutide activity in conditions connected with neuronal damage, with special emphasis on Alzheimer’s disease and cerebral ischemia. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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19 pages, 770 KiB

Open AccessReview

Etiology of Metabolic Syndrome and Dietary Intervention

by Hang Xu, Xiaopeng Li, Hannah Adams, Karen Kubena and Shaodong Guo

Int. J. Mol. Sci. 2019, 20(1), 128; https://doi.org/10.3390/ijms20010128 - 31 Dec 2018

Cited by 152 | Viewed by 19234

Abstract

The growing prevalence of metabolic syndrome (MetS) in the U.S. and even worldwide is becoming a serious health problem and economic burden. MetS has become a crucial risk factor for the development of type 2 diabetes mellitus (T2D) and cardiovascular diseases (CVD). The [...] Read more.

The growing prevalence of metabolic syndrome (MetS) in the U.S. and even worldwide is becoming a serious health problem and economic burden. MetS has become a crucial risk factor for the development of type 2 diabetes mellitus (T2D) and cardiovascular diseases (CVD). The rising rates of CVD and diabetes, which are the two leading causes of death, simultaneously exist. To prevent the progression of MetS to diabetes and CVD, we have to understand how MetS occurs and how it progresses. Too many causative factors interact with each other, making the investigation and treatment of metabolic syndrome a very complex issue. Recently, a number of studies were conducted to investigate mechanisms and interventions of MetS, from different aspects. In this review, the proposed and demonstrated mechanisms of MetS pathogenesis are discussed and summarized. More importantly, different interventions are discussed, so that health practitioners can have a better understanding of the most recent research progress and have available references for their daily practice. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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