Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions

ABSTRACTMicrotubules are biopolymers that perform diverse cellular functions. The regulation of microtubule behavior occurs in part through post-translational modification of both the α- and β- subunits of tubulin. One class of modifications is the heterogeneous addition of glycine and glutamate residues to the disordered C-terminal tails of tubulin. Due to their prevalence in stable, high stress cellular structures such as cilia, we sought to determine if these modifications alter the intrinsic stiffness of microtubules. Here we describe the purification and characterization of differentially-modified pools of tubulin from Tetrahymena thermophila. We found that glycylation on the α-C-terminal tail is a key determinant of microtubule stiffness, but does not affect the number of protofilaments incorporated into microtubules. We measured the dynamics of the tail peptide backbone using nuclear magnetic resonance spectroscopy. We found that the spin-spin relaxation rate (R2) showed a pronounced decreased as a function of distance from the tubulin surface for the α-tubulin tail, indicating that the α-tubulin tail interacts with the dimer surface. This suggests that the interactions of the α-C-terminal tail with the tubulin body contributes to the stiffness of the assembled microtubule, providing insight into the mechanism by which glycylation and glutamylation can alter microtubule mechanical properties.SIGNIFICANCEMicrotubules are regulated in part by post-translational modifications including the heterogeneous addition of glycine and glutamate residues to the C-terminal tails. By producing and characterizing differentially-modified tubulin, this work provides insight into the molecular mechanisms of how these modifications alter intrinsic microtubule properties such as flexibility. These results have broader implications for mechanisms of how ciliary structures are able to function under high stress.

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New Insight into Molecular and Hormonal Connection in Andrology

International Journal of Molecular Sciences ◽

10.3390/ijms222111908 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11908

Author(s):

Davide Francomano ◽

Valerio Sanguigni ◽

Paolo Capogrosso ◽

Federico Deho ◽

Gabriele Antonini

Keyword(s):

Sexual Function ◽

Molecular Mechanisms ◽

Vascular Wall ◽

Cell Junction ◽

Testicular Development ◽

Cellular Functions ◽

Inflammatory Site ◽

Male Sexual Function ◽

Molecular Patterns ◽

Insight Into

Hormones and cytokines are known to regulate cellular functions in the testes. These biomolecules induce a broad spectrum of effects on various level of spermatogenesis, and among them is the modulation of cell junction restructuring between Sertoli cells and germ cells in the seminiferous epithelium. Cytokines and androgens are closely related, and both correct testicular development and the maintenance of spermatogenesis depend on their function. Cytokines also play a crucial role in the immune testicular system, activating and directing leucocytes across the endothelial barrier to the inflammatory site, as well as in increasing their adhesion to the vascular wall. The purpose of this review is to revise the most recent findings on molecular mechanisms that play a key role in male sexual function, focusing on three specific molecular patterns, namely, cytokines, miRNAs, and endothelial progenitor cells. Numerous reports on the interactions between the immune and endocrine systems can be found in the literature. However, there is not yet a multi-approach review of the literature underlying the role between molecular patterns and testicular and sexual function.

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Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

Cancers ◽

10.3390/cancers13040795 ◽

2021 ◽

Vol 13 (4) ◽

pp. 795

Author(s):

Lukas Gorecki ◽

Martin Andrs ◽

Jan Korabecny

Keyword(s):

Cell Cycle ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Patient Survival ◽

Current Status ◽

Future Perspectives ◽

Phase Ii Trials ◽

Anticancer Treatment ◽

Positive Outlook ◽

Insight Into

Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra‑S or G2/M checkpoints has also been extensively pursued. This review focuses on clinical candidates that target the kinases involved in intra‑S and G2/M checkpoints, namely, ATR, CHK1, and WEE1 inhibitors. It provides insight into their current status and future perspectives for anticancer treatment. Overall, even though CHK1 inhibitors are still far from clinical establishment, promising accomplishments with ATR and WEE1 inhibitors in phase II trials present a positive outlook for patient survival.

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Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Genes ◽

10.3390/genes12081150 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1150

Author(s):

Jana Tomc ◽

Nataša Debeljak

Keyword(s):

Signal Transduction ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Oxygen Affinity ◽

Molecular Pathways ◽

Disease Development ◽

Post Translational Modifications ◽

Hemoglobin Oxygen Affinity ◽

Insight Into ◽

Idiopathic Erythrocytosis

Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

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Pathomechanisms in the Kidneys in Selected Protozoan Parasitic Infections

International Journal of Molecular Sciences ◽

10.3390/ijms22084209 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4209

Author(s):

Karolina Kot ◽

Natalia Łanocha-Arendarczyk ◽

Michał Ptak ◽

Aleksandra Łanocha ◽

Elżbieta Kalisińska ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Molecular Mechanisms ◽

Kidney Injury ◽

Therapeutic Interventions ◽

Parasitic Infections ◽

Injury Mechanisms ◽

Kidney Involvement ◽

Leishmania Spp ◽

Apoptosis Process ◽

Insight Into

Leishmaniasis, malaria, toxoplasmosis, and acanthamoebiasis are protozoan parasitic infections. They remain important contributors to the development of kidney disease, which is associated with increased patients’ morbidity and mortality. Kidney injury mechanisms are not fully understood in protozoan parasitic diseases, bringing major difficulties to specific therapeutic interventions. The aim of this review is to present the biochemical and molecular mechanisms in kidneys infected with Leishmania spp., Plasmodium spp., Toxoplasma gondii, and Acanthamoeba spp. We present available mechanisms of an immune response, oxidative stress, apoptosis process, hypoxia, biomarkers of renal injury in the serum or urine, and the histopathological changes of kidneys infected with the selected parasites. Pathomechanisms of Leishmania spp. and Plasmodium spp. infections have been deeply investigated, while Toxoplasma gondii and Acanthamoeba spp. infections in the kidneys are not well known yet. Deeper knowledge of kidney involvement in leishmaniasis and malaria by presenting their mechanisms provides insight into how to create novel and effective treatments. Additionally, the presented work shows gaps in the pathophysiology of renal toxoplasmosis and acanthamoebiasis, which need further research.

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The apple C2H2-type zinc finger transcription factor MdZAT10 positively regulates JA-induced leaf senescence by interacting with MdBT2

Horticulture Research ◽

10.1038/s41438-021-00593-0 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Kuo Yang ◽

Jian-Ping An ◽

Chong-Yang Li ◽

Xue-Na Shen ◽

Ya-Jing Liu ◽

...

Keyword(s):

Mass Spectrometry ◽

Transcription Factor ◽

Liquid Chromatography ◽

Zinc Finger ◽

Leaf Senescence ◽

Transcriptional Activity ◽

Molecular Mechanisms ◽

Liquid Chromatography Mass Spectrometry ◽

Zinc Finger Transcription Factor ◽

Insight Into

AbstractJasmonic acid (JA) plays an important role in regulating leaf senescence. However, the molecular mechanisms of leaf senescence in apple (Malus domestica) remain elusive. In this study, we found that MdZAT10, a C2H2-type zinc finger transcription factor (TF) in apple, markedly accelerates leaf senescence and increases the expression of senescence-related genes. To explore how MdZAT10 promotes leaf senescence, we carried out liquid chromatography/mass spectrometry screening. We found that MdABI5 physically interacts with MdZAT10. MdABI5, an important positive regulator of leaf senescence, significantly accelerated leaf senescence in apple. MdZAT10 was found to enhance the transcriptional activity of MdABI5 for MdNYC1 and MdNYE1, thus accelerating leaf senescence. In addition, we found that MdZAT10 expression was induced by methyl jasmonate (MeJA), which accelerated JA-induced leaf senescence. We also found that the JA-responsive protein MdBT2 directly interacts with MdZAT10 and reduces its protein stability through ubiquitination and degradation, thereby delaying MdZAT10-mediated leaf senescence. Taken together, our results provide new insight into the mechanisms by which MdZAT10 positively regulates JA-induced leaf senescence in apple.

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Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

Life ◽

10.3390/life11040332 ◽

2021 ◽

Vol 11 (4) ◽

pp. 332

Author(s):

Valentina Brillo ◽

Leonardo Chieregato ◽

Luigi Leanza ◽

Silvia Muccioli ◽

Roberto Costa

Keyword(s):

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Eukaryotic Cells ◽

Therapeutic Approaches ◽

Cellular Functions ◽

Lipid Trafficking ◽

Mitochondrial Ros ◽

Intracellular Organelles ◽

Proliferation Regulation ◽

Dynamic Plasticity

Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute to the dynamic plasticity of their network, also strongly influenced by mitochondrial contacts with other subcellular organelles. Nevertheless, mitochondria release a major amount of reactive oxygen species (ROS) inside eukaryotic cells, which are reported to mediate a plethora of both physiological and pathological cellular functions, such as growth and proliferation, regulation of autophagy, apoptosis, and metastasis. Therefore, targeting mitochondrial ROS could be a promising strategy to overcome and hinder the development of diseases such as cancer, where malignant cells, possessing a higher amount of ROS with respect to healthy ones, could be specifically targeted by therapeutic treatments. In this review, we collected the ultimate findings on the blended interplay among mitochondrial shaping, mitochondrial ROS, and several signaling pathways, in order to contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology of eukaryotic cells, possibly improving future therapeutic approaches.

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Cold-Active β-Galactosidases: Insight into Cold Adaption Mechanisms and Biotechnological Exploitation

Marine Drugs ◽

10.3390/md19010043 ◽

2021 ◽

Vol 19 (1) ◽

pp. 43

Author(s):

Marco Mangiagalli ◽

Marina Lotti

Keyword(s):

Low Temperature ◽

Molecular Mechanisms ◽

Building Blocks ◽

Cold Active ◽

Cold Adaption ◽

Glycosyl Donor ◽

Pharmaceutical Industries ◽

Biotechnological Processes ◽

Hydrolysis Of ◽

Insight Into

β-galactosidases (EC 3.2.1.23) catalyze the hydrolysis of β-galactosidic bonds in oligosaccharides and, under certain conditions, transfer a sugar moiety from a glycosyl donor to an acceptor. Cold-active β-galactosidases are identified in microorganisms endemic to permanently low-temperature environments. While mesophilic β-galactosidases are broadly studied and employed for biotechnological purposes, the cold-active enzymes are still scarcely explored, although they may prove very useful in biotechnological processes at low temperature. This review covers several issues related to cold-active β-galactosidases, including their classification, structure and molecular mechanisms of cold adaptation. Moreover, their applications are discussed, focusing on the production of lactose-free dairy products as well as on the valorization of cheese whey and the synthesis of glycosyl building blocks for the food, cosmetic and pharmaceutical industries.

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Integrated Insight into the Molecular Mechanisms of Spontaneous Abortion during Early Pregnancy in Pigs

International Journal of Molecular Sciences ◽

10.3390/ijms22126644 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6644

Author(s):

Xupeng Zang ◽

Ting Gu ◽

Wenjing Wang ◽

Chen Zhou ◽

Yue Ding ◽

...

Keyword(s):

Immune Response ◽

Spontaneous Abortion ◽

Molecular Mechanisms ◽

Gene Set Enrichment Analysis ◽

Differentially Expressed ◽

Gene Set ◽

Cerna Network ◽

Major Interest ◽

End Stage ◽

Insight Into

Due to the high rate of spontaneous abortion (SAB) in porcine pregnancy, there is a major interest and concern on commercial pig farming worldwide. Whereas the perturbed immune response at the maternal–fetal interface is an important mechanism associated with the spontaneous embryo loss in the early stages of implantation in porcine, data on the specific regulatory mechanism of the SAB at the end stage of the implantation remains scant. Therefore, we used high-throughput sequencing and bioinformatics tools to analyze the healthy and arresting endometrium on day 28 of pregnancy. We identified 639 differentially expressed lncRNAs (DELs) and 2357 differentially expressed genes (DEGs) at the end stage of implantation, and qRT-PCR was used to verify the sequencing data. Gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immunohistochemistry analysis demonstrated weaker immune response activities in the arresting endometrium compared to the healthy one. Using the lasso regression analysis, we screened the DELs and constructed an immunological competitive endogenous RNA (ceRNA) network related to SAB, including 4 lncRNAs, 11 miRNAs, and 13 genes. In addition, Blast analysis showed the applicability of the constructed ceRNA network in different species, and subsequently determined HOXA-AS2 in pigs. Our study, for the first time, demonstrated that the SAB events at the end stages of implantation is associated with the regulation of immunobiological processes, and a specific molecular regulatory network was obtained. These novel findings may provide new insight into the possibility of increasing the litter size of sows, making pig breeding better and thus improving the efficiency of animal husbandry production.

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