Cells

Review

38 pages, 8855 KiB

Open AccessReview

Cardiovascular Functions of Ena/VASP Proteins: Past, Present and Beyond

by Peter M. Benz, Timo Frömel, Hebatullah Laban, Joana Zink, Lea Ulrich, Dieter Groneberg, Reinier A. Boon, Philip Poley, Thomas Renne, Cor de Wit and Ingrid Fleming

Cells 2023, 12(13), 1740; https://doi.org/10.3390/cells12131740 - 28 Jun 2023

Cited by 1 | Viewed by 1591

Abstract

Actin binding proteins are of crucial importance for the spatiotemporal regulation of actin cytoskeletal dynamics, thereby mediating a tremendous range of cellular processes. Since their initial discovery more than 30 years ago, the enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family has evolved as one of the [...] Read more.

Actin binding proteins are of crucial importance for the spatiotemporal regulation of actin cytoskeletal dynamics, thereby mediating a tremendous range of cellular processes. Since their initial discovery more than 30 years ago, the enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family has evolved as one of the most fascinating and versatile family of actin regulating proteins. The proteins directly enhance actin filament assembly, but they also organize higher order actin networks and link kinase signaling pathways to actin filament assembly. Thereby, Ena/VASP proteins regulate dynamic cellular processes ranging from membrane protrusions and trafficking, and cell-cell and cell-matrix adhesions, to the generation of mechanical tension and contractile force. Important insights have been gained into the physiological functions of Ena/VASP proteins in platelets, leukocytes, endothelial cells, smooth muscle cells and cardiomyocytes. In this review, we summarize the unique and redundant functions of Ena/VASP proteins in cardiovascular cells and discuss the underlying molecular mechanisms. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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21 pages, 1153 KiB

Open AccessReview

A Plethora of Functions Condensed into Tiny Phospholipids: The Story of PI4P and PI(4,5)P₂

by Ana Bura, Sara Čabrijan, Iris Đurić, Tea Bruketa and Antonija Jurak Begonja

Cells 2023, 12(10), 1411; https://doi.org/10.3390/cells12101411 - 17 May 2023

Cited by 2 | Viewed by 1873

Abstract

Phosphoinositides (PIs) are small, phosphorylated lipids that serve many functions in the cell. They regulate endo- and exocytosis, vesicular trafficking, actin reorganization, and cell mobility, and they act as signaling molecules. The most abundant PIs in the cell are phosphatidylinositol-4-monophosphate (PI4P) and phosphatidylinositol-4,5-bisphosphate [...] Read more.

Phosphoinositides (PIs) are small, phosphorylated lipids that serve many functions in the cell. They regulate endo- and exocytosis, vesicular trafficking, actin reorganization, and cell mobility, and they act as signaling molecules. The most abundant PIs in the cell are phosphatidylinositol-4-monophosphate (PI4P) and phosphatidylinositol-4,5-bisphosphate [PI(4,5)P₂]. PI4P is mostly localized at the Golgi apparatus where it regulates the anterograde trafficking from the Golgi apparatus to the plasma membrane (PM), but it also localizes at the PM. On the other hand, the main localization site of PI(4,5)P₂ is the PM where it regulates the formation of endocytic vesicles. The levels of PIs are regulated by many kinases and phosphatases. Four main kinases phosphorylate the precursor molecule phosphatidylinositol into PI4P, divided into two classes (PI4KIIα, PI4KIIβ, PI4KIIIα, and PI4KIIIβ), and three main kinases phosphorylate PI4P to form PI(4,5)P₂ (PI4P5KIα, PI4P5KIβ, and PI4P5KIγ). In this review, we discuss the localization and function of the kinases that produce PI4P and PI(4,5)P₂, as well as the localization and function of their product molecules with an overview of tools for the detection of these PIs. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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12 pages, 640 KiB

Open AccessReview

Multiple Roles of cAMP in Vertebrate Retina

by Natalia Erofeeva, Darya Meshalkina and Michael Firsov

Cells 2023, 12(8), 1157; https://doi.org/10.3390/cells12081157 - 14 Apr 2023

Cited by 3 | Viewed by 1649

Abstract

cAMP is a key regulatory molecule that controls many important processes in the retina, including phototransduction, cell development and death, growth of neural processes, intercellular contacts, retinomotor effects, and so forth. The total content of cAMP changes in the retina in a circadian [...] Read more.

cAMP is a key regulatory molecule that controls many important processes in the retina, including phototransduction, cell development and death, growth of neural processes, intercellular contacts, retinomotor effects, and so forth. The total content of cAMP changes in the retina in a circadian manner following the natural light cycle, but it also shows local and even divergent changes in faster time scales in response to local and transient changes in the light environment. Changes in cAMP might also manifest or cause various pathological processes in virtually all cellular components of the retina. Here we review the current state of knowledge and understanding of the regulatory mechanisms by which cAMP influences the physiological processes that occur in various retinal cells. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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29 pages, 7001 KiB

Open AccessReview

Mechanisms of Blood–Brain Barrier Protection by Microbiota-Derived Short-Chain Fatty Acids

by Ekaterina Fock and Rimma Parnova

Cells 2023, 12(4), 657; https://doi.org/10.3390/cells12040657 - 18 Feb 2023

Cited by 28 | Viewed by 4864

Abstract

Impairment of the blood–brain barrier (BBB) integrity is implicated in the numerous neurological disorders associated with neuroinflammation, neurodegeneration and aging. It is now evident that short-chain fatty acids (SCFAs), mainly acetate, butyrate and propionate, produced by anaerobic bacterial fermentation of the dietary fiber [...] Read more.

Impairment of the blood–brain barrier (BBB) integrity is implicated in the numerous neurological disorders associated with neuroinflammation, neurodegeneration and aging. It is now evident that short-chain fatty acids (SCFAs), mainly acetate, butyrate and propionate, produced by anaerobic bacterial fermentation of the dietary fiber in the intestine, have a key role in the communication between the gastrointestinal tract and nervous system and are critically important for the preservation of the BBB integrity under different pathological conditions. The effect of SCFAs on the improvement of the compromised BBB is mainly based on the decrease in paracellular permeability via restoration of junctional complex proteins affecting their transcription, intercellular localization or proteolytic degradation. This review is focused on the revealed and putative underlying mechanisms of the direct and indirect effects of SCFAs on the improvement of the barrier function of brain endothelial cells. We consider G-protein-coupled receptor-mediated effects of SCFAs, SCFAs-stimulated acetylation of histone and non-histone proteins via inhibition of histone deacetylases, and crosstalk of these signaling pathways with transcriptional factors NF-κB and Nrf2 as mainstream mechanisms of SCFA’s effect on the preservation of the BBB integrity. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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17 pages, 4600 KiB

Open AccessReview

Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics

by Vanessa M. Ruscetta, Taj J. Seaton, Aleen Shakeel, Stanley N. S. Vasconcelos, Russell D. Viirre, Marc J. Adler and Michael F. Olson

Cells 2023, 12(4), 534; https://doi.org/10.3390/cells12040534 - 07 Feb 2023

Viewed by 2127

Abstract

Cytoskeleton organization and dynamics are rapidly regulated by post-translational modifications of key target proteins. Acting downstream of the Cdc42 GTPase, the myotonic dystrophy-related Cdc42-binding kinases MRCKα, MRCKβ, and MRCKγ have recently emerged as important players in cytoskeleton regulation through the phosphorylation of proteins [...] Read more.

Cytoskeleton organization and dynamics are rapidly regulated by post-translational modifications of key target proteins. Acting downstream of the Cdc42 GTPase, the myotonic dystrophy-related Cdc42-binding kinases MRCKα, MRCKβ, and MRCKγ have recently emerged as important players in cytoskeleton regulation through the phosphorylation of proteins such as the regulatory myosin light chain proteins. Compared with the closely related Rho-associated coiled-coil kinases 1 and 2 (ROCK1 and ROCK2), the contributions of the MRCK kinases are less well characterized, one reason for this being that the discovery of potent and selective MRCK pharmacological inhibitors occurred many years after the discovery of ROCK inhibitors. The disclosure of inhibitors, such as BDP5290 and BDP9066, that have marked selectivity for MRCK over ROCK, as well as the dual ROCK + MRCK inhibitor DJ4, has expanded the repertoire of chemical biology tools to study MRCK function in normal and pathological conditions. Recent research has used these novel inhibitors to establish the role of MRCK signalling in epithelial polarization, phagocytosis, cytoskeleton organization, cell motility, and cancer cell invasiveness. Furthermore, pharmacological MRCK inhibition has been shown to elicit therapeutically beneficial effects in cell-based and in vivo studies of glioma, skin, and ovarian cancers. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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17 pages, 925 KiB

Open AccessReview

Cellular Factors That Shape the Activity or Function of Nitric Oxide-Stimulated Soluble Guanylyl Cyclase

by Iraida Sharina and Emil Martin

Cells 2023, 12(3), 471; https://doi.org/10.3390/cells12030471 - 01 Feb 2023

Cited by 2 | Viewed by 1770

Abstract

NO-stimulated guanylyl cyclase (SGC) is a hemoprotein that plays key roles in various physiological functions. SGC is a typical enzyme-linked receptor that combines the functions of a sensor for NO gas and cGMP generator. SGC possesses exclusive selectivity for NO and exhibits a [...] Read more.

NO-stimulated guanylyl cyclase (SGC) is a hemoprotein that plays key roles in various physiological functions. SGC is a typical enzyme-linked receptor that combines the functions of a sensor for NO gas and cGMP generator. SGC possesses exclusive selectivity for NO and exhibits a very fast binding of NO, which allows it to function as a sensitive NO receptor. This review describes the effect of various cellular factors, such as additional NO, cell thiols, cell-derived small molecules and proteins on the function of SGC as cellular NO receptor. Due to its vital physiological function SGC is an important drug target. An increasing number of synthetic compounds that affect SGC activity via different mechanisms are discovered and brought to clinical trials and clinics. Cellular factors modifying the activity of SGC constitute an opportunity for improving the effectiveness of existing SGC-directed drugs and/or the creation of new therapeutic strategies. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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23 pages, 1359 KiB

Open AccessReview

Voltage-Gated T-Type Calcium Channel Modulation by Kinases and Phosphatases: The Old Ones, the New Ones, and the Missing Ones

by Ankush Sharma, Ghazala Rahman, Julia Gorelik and Anamika Bhargava

Cells 2023, 12(3), 461; https://doi.org/10.3390/cells12030461 - 31 Jan 2023

Cited by 5 | Viewed by 2656

Abstract

Calcium (Ca²⁺) can regulate a wide variety of cellular fates, such as proliferation, apoptosis, and autophagy. More importantly, changes in the intracellular Ca²⁺ level can modulate signaling pathways that control a broad range of physiological as well as pathological cellular [...] Read more.

Calcium (Ca²⁺) can regulate a wide variety of cellular fates, such as proliferation, apoptosis, and autophagy. More importantly, changes in the intracellular Ca²⁺ level can modulate signaling pathways that control a broad range of physiological as well as pathological cellular events, including those important to cellular excitability, cell cycle, gene-transcription, contraction, cancer progression, etc. Not only intracellular Ca²⁺ level but the distribution of Ca²⁺ in the intracellular compartments is also a highly regulated process. For this Ca²⁺ homeostasis, numerous Ca²⁺ chelating, storage, and transport mechanisms are required. There are also specialized proteins that are responsible for buffering and transport of Ca²⁺. T-type Ca²⁺ channels (TTCCs) are one of those specialized proteins which play a key role in the signal transduction of many excitable and non-excitable cell types. TTCCs are low-voltage activated channels that belong to the family of voltage-gated Ca²⁺ channels. Over decades, multiple kinases and phosphatases have been shown to modulate the activity of TTCCs, thus playing an indirect role in maintaining cellular physiology. In this review, we provide information on the kinase and phosphatase modulation of TTCC isoforms Cav3.1, Cav3.2, and Cav3.3, which are mostly described for roles unrelated to cellular excitability. We also describe possible potential modulations that are yet to be explored. For example, both mitogen-activated protein kinase and citron kinase show affinity for different TTCC isoforms; however, the effect of such interaction on TTCC current/kinetics has not been studied yet. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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12 pages, 1298 KiB

Open AccessReview

A-Kinase Anchoring Proteins in Cardiac Myocytes and Their Roles in Regulating Calcium Cycling

by Hariharan Subramanian and Viacheslav O. Nikolaev

Cells 2023, 12(3), 436; https://doi.org/10.3390/cells12030436 - 28 Jan 2023

Cited by 3 | Viewed by 2187

Abstract

The rate of calcium cycling and calcium transient amplitude are critical determinants for the efficient contraction and relaxation of the heart. Calcium-handling proteins in the cardiac myocyte are altered in heart failure, and restoring the proper function of those proteins is an effective [...] Read more.

The rate of calcium cycling and calcium transient amplitude are critical determinants for the efficient contraction and relaxation of the heart. Calcium-handling proteins in the cardiac myocyte are altered in heart failure, and restoring the proper function of those proteins is an effective potential therapeutic strategy. The calcium-handling proteins or their regulators are phosphorylated by a cAMP-dependent kinase (PKA), and thereby their activity is regulated. A-Kinase Anchoring Proteins (AKAPs) play a seminal role in orchestrating PKA and cAMP regulators in calcium handling and contractile machinery. This cAMP/PKA orchestration is crucial for the increased force and rate of contraction and relaxation of the heart in response to fight-or-flight. Knockout models and the few available preclinical models proved that the efficient targeting of AKAPs offers potential therapies tailor-made for improving defective calcium cycling. In this review, we highlight important studies that identified AKAPs and their regulatory roles in cardiac myocyte calcium cycling in health and disease. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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24 pages, 930 KiB

Open AccessReview

Intercommunication between Voltage-Gated Calcium Channels and Estrogen Receptor/Estrogen Signaling: Insights into Physiological and Pathological Conditions

by Yashashwini Dinesh Subbamanda and Anamika Bhargava

Cells 2022, 11(23), 3850; https://doi.org/10.3390/cells11233850 - 30 Nov 2022

Cited by 3 | Viewed by 2274

Abstract

Voltage-gated calcium channels (VGCCs) and estrogen receptors are important cellular proteins that have been shown to interact with each other across varied cells and tissues. Estrogen hormone, the ligand for estrogen receptors, can also exert its effects independent of estrogen receptors that collectively [...] Read more.

Voltage-gated calcium channels (VGCCs) and estrogen receptors are important cellular proteins that have been shown to interact with each other across varied cells and tissues. Estrogen hormone, the ligand for estrogen receptors, can also exert its effects independent of estrogen receptors that collectively constitute non-genomic mechanisms. Here, we provide insights into the VGCC regulation by estrogen and the possible mechanisms involved therein across several cell types. Notably, most of the interaction is described in neuronal and cardiovascular tissues given the importance of VGCCs in these electrically excitable tissues. We describe the modulation of various VGCCs by estrogen known so far in physiological conditions and pathological conditions. We observed that in most in vitro studies higher concentrations of estrogen were used while a handful of in vivo studies used meager concentrations resulting in inhibition or upregulation of VGCCs, respectively. There is a need for more relevant physiological assays to study the regulation of VGCCs by estrogen. Additionally, other interacting receptors and partners need to be identified that may be involved in exerting estrogen receptor-independent effects of estrogen. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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12 pages, 1964 KiB

Open AccessFeature PaperReview

LASP1 in Cellular Signaling and Gene Expression: More than Just a Cytoskeletal Regulator

by Elke Butt, Cory M. Howard and Dayanidhi Raman

Cells 2022, 11(23), 3817; https://doi.org/10.3390/cells11233817 - 29 Nov 2022

Cited by 6 | Viewed by 1810

Abstract

LIM and SH3 protein 1 was originally identified as a structural cytoskeletal protein with scaffolding function. However, recent data suggest additional roles in cell signaling and gene expression, especially in tumor cells. These novel functions are primarily regulated by the site-specific phosphorylation of [...] Read more.

LIM and SH3 protein 1 was originally identified as a structural cytoskeletal protein with scaffolding function. However, recent data suggest additional roles in cell signaling and gene expression, especially in tumor cells. These novel functions are primarily regulated by the site-specific phosphorylation of LASP1. This review will focus on specific phosphorylation-dependent interaction between LASP1 and cellular proteins that orchestrate primary tumor progression and metastasis. More specifically, we will describe the role of LASP1 in chemokine receptor, and PI3K/AKT signaling. We outline the nuclear role for LASP1 in terms of epigenetics and transcriptional regulation and modulation of oncogenic mRNA translation. Finally, newly identified roles for the cytoskeletal function of LASP1 next to its known canonical F-actin binding properties are included. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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20 pages, 1419 KiB

Open AccessReview

The Role of NO/sGC/cGMP/PKG Signaling Pathway in Regulation of Platelet Function

by Stepan Gambaryan

Cells 2022, 11(22), 3704; https://doi.org/10.3390/cells11223704 - 21 Nov 2022

Cited by 13 | Viewed by 3155

Abstract

Circulating blood platelets are controlled by stimulatory and inhibitory factors, and a tightly regulated equilibrium between these two opposing processes is essential for normal platelet and vascular function. NO/cGMP/ Protein Kinase G (PKG) pathways play a highly significant role in platelet inhibition, which [...] Read more.

Circulating blood platelets are controlled by stimulatory and inhibitory factors, and a tightly regulated equilibrium between these two opposing processes is essential for normal platelet and vascular function. NO/cGMP/ Protein Kinase G (PKG) pathways play a highly significant role in platelet inhibition, which is supported by a large body of studies and data. This review focused on inconsistent and controversial data of NO/sGC/cGMP/PKG signaling in platelets including sources of NO that activate sGC in platelets, the role of sGC/PKG in platelet inhibition/activation, and the complexity of the regulation of platelet inhibitory mechanisms by cGMP/PKG pathways. In conclusion, we suggest that the recently developed quantitative phosphoproteomic method will be a powerful tool for the analysis of PKG-mediated effects. Analysis of phosphoproteins in PKG-activated platelets will reveal many new PKG substrates. A future detailed analysis of these substrates and their involvement in different platelet inhibitory pathways could be a basis for the development of new antiplatelet drugs that may target only specific aspects of platelet functions. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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37 pages, 4113 KiB

Open AccessReview

Signaling by LncRNAs: Structure, Cellular Homeostasis, and Disease Pathology

by Revathy Nadhan, Ciro Isidoro, Yong Sang Song and Danny N. Dhanasekaran

Cells 2022, 11(16), 2517; https://doi.org/10.3390/cells11162517 - 13 Aug 2022

Cited by 16 | Viewed by 2778

Abstract

The cellular signaling network involves co-ordinated regulation of numerous signaling molecules that aid the maintenance of cellular as well as organismal homeostasis. Aberrant signaling plays a major role in the pathophysiology of many diseases. Recent studies have unraveled the superfamily of long non-coding [...] Read more.

The cellular signaling network involves co-ordinated regulation of numerous signaling molecules that aid the maintenance of cellular as well as organismal homeostasis. Aberrant signaling plays a major role in the pathophysiology of many diseases. Recent studies have unraveled the superfamily of long non-coding RNAs (lncRNAs) as critical signaling nodes in diverse signaling networks. Defective signaling by lncRNAs is emerging as a causative factor underlying the pathophysiology of many diseases. LncRNAs have been shown to be involved in the multiplexed regulation of diverse pathways through both genetic and epigenetic mechanisms. They can serve as decoys, guides, scaffolds, and effector molecules to regulate cell signaling. In comparison with the other classes of RNAs, lncRNAs possess unique structural modifications that contribute to their diversity in modes of action within the nucleus and cytoplasm. In this review, we summarize the structure and function of lncRNAs as well as their vivid mechanisms of action. Further, we provide insights into the role of lncRNAs in the pathogenesis of four major disease paradigms, namely cardiovascular diseases, neurological disorders, cancers, and the metabolic disease, diabetes mellitus. This review serves as a succinct treatise that could open windows to investigate the role of lncRNAs as novel therapeutic targets. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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