Who does TORC2 talk to?

2018 ◽  
Vol 475 (10) ◽  
pp. 1721-1738 ◽  
Author(s):  
Jianling Xie ◽  
Xuemin Wang ◽  
Christopher G. Proud
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Gene Transcription ◽  
Cell Metabolism ◽  
Cellular Functions ◽  
Cellular Physiology ◽  
Cell Functions ◽  
Wide Range ◽  
And Control ◽  
Partner Proteins

The target of rapamycin (TOR) is a protein kinase that, by forming complexes with partner proteins, governs diverse cellular signalling networks to regulate a wide range of processes. TOR thus plays central roles in maintaining normal cellular functions and, when dysregulated, in diverse diseases. TOR forms two distinct types of multiprotein complexes (TOR complexes 1 and 2, TORC1 and TORC2). TORC1 and TORC2 differ in their composition, their control and their substrates, so that they play quite distinct roles in cellular physiology. Much effort has been focused on deciphering the detailed regulatory links within the TOR pathways and the structure and control of TOR complexes. In this review, we summarize recent advances in understanding mammalian (m) TORC2, its structure, its regulation, and its substrates, which link TORC2 signalling to the control of cell functions. It is now clear that TORC2 regulates several aspects of cell metabolism, including lipogenesis and glucose transport. It also regulates gene transcription, the cytoskeleton, and the activity of a subset of other protein kinases.

scholarly journals Ca2+ Microdomains, Calcineurin and the Regulation of Gene Transcription

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 875
Author(s):  
Gerald Thiel ◽  
Tobias Schmidt ◽  
Oliver G. Rössler
Keyword(s):  
Transcription Factors ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Gene Transcription ◽  
Intracellular Signaling ◽  
Second Messengers ◽  
Major Function ◽  
Surface Receptors ◽  
Dependent Protein

Ca2+ ions function as second messengers regulating many intracellular events, including neurotransmitter release, exocytosis, muscle contraction, metabolism and gene transcription. Cells of a multicellular organism express a variety of cell-surface receptors and channels that trigger an increase of the intracellular Ca2+ concentration upon stimulation. The elevated Ca2+ concentration is not uniformly distributed within the cytoplasm but is organized in subcellular microdomains with high and low concentrations of Ca2+ at different locations in the cell. Ca2+ ions are stored and released by intracellular organelles that change the concentration and distribution of Ca2+ ions. A major function of the rise in intracellular Ca2+ is the change of the genetic expression pattern of the cell via the activation of Ca2+-responsive transcription factors. It has been proposed that Ca2+-responsive transcription factors are differently affected by a rise in cytoplasmic versus nuclear Ca2+. Moreover, it has been suggested that the mode of entry determines whether an influx of Ca2+ leads to the stimulation of gene transcription. A rise in cytoplasmic Ca2+ induces an intracellular signaling cascade, involving the activation of the Ca2+/calmodulin-dependent protein phosphatase calcineurin and various protein kinases (protein kinase C, extracellular signal-regulated protein kinase, Ca2+/calmodulin-dependent protein kinases). In this review article, we discuss the concept of gene regulation via elevated Ca2+ concentration in the cytoplasm and the nucleus, the role of Ca2+ entry and the role of enzymes as signal transducers. We give particular emphasis to the regulation of gene transcription by calcineurin, linking protein dephosphorylation with Ca2+ signaling and gene expression.

scholarly journals Vanadium oxoanions and cAMP-dependent protein kinase: an anti-substrate inhibitor

1997 ◽  
Vol 321 (2) ◽  
pp. 333-339 ◽  
Author(s):  
Scott PLUSKEY ◽  
Mohammad MAHROOF-TAHIR ◽  
Debbie C. CRANS ◽  
David S. LAWRENCE
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Competitive Inhibitor ◽  
Serine Threonine Kinase ◽  
Dependent Protein Kinase ◽  
Phosphorylated Proteins ◽  
Camp Dependent Protein Kinase ◽  
Wide Range ◽  
Dependent Protein ◽  
Substrate Inhibitor

Vanadium oxoions have been shown to elicit a wide range of effects in biological systems, including an increase in the quantity of phosphorylated proteins. This response has been attributed to the inhibition of protein phosphatases, the indirect activation of protein kinases via stimulation of enzymes at early steps in signal transduction pathways and/or the direct activation of protein kinases. We have evaluated the latter possibility by exploring the effects of vanadate, decavanadate and vanadyl cation species on the activity of the cAMP-dependent protein kinase (PKA), a serine/threonine kinase. Vanadate, in the form of monomer, dimer, tetramer and pentamer species, neither inhibits nor activates PKA. In marked contrast, decavanadate is a competitive inhibitor (Ki = 1.8ŷ0.1 mM) of kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly), a peptide-based substrate. This inhibition pattern is especially surprising, since the negatively charged decavanadate would not be predicted to bind to the region of the active site of the enzyme that accommodates the positively charged kemptide substrate. Our studies suggest that decavanadate can associate with kemptide in solution, which would prevent kemptide from interacting with the enzyme. Vanadium(IV) also inhibits the PKA-catalysed phosphorylation of kemptide, but with an IC50 of 366ŷ10 ƁM. However, in this case V4+ appears to bind to the Mg2+-binding site, since it can substitute for Mg2+. In the absence of Mg2+, the optimal concentration of vanadium(IV) for the PKA-catalysed phosphorylation of kemptide is 100 ƁM, with concentrations above 100 ƁM being markedly inhibitory. However, even at the optimal 100 ƁM V4+ concentration, the Vmax and Km values (for kemptide) are significantly less favourable than those obtained in the presence of 100 ƁM Mg2+. In summary, we have found that oxovanadium ions can directly alter the activity of the serine/threonine-specific PKA.

Actin cytoskeletal dynamics in smooth muscle contraction

2005 ◽  
Vol 83 (10) ◽  
pp. 851-856 ◽  
Author(s):  
William T Gerthoffer
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Actin Cytoskeleton ◽  
Protein Kinases ◽  
Smooth Muscles ◽  
Small Gtpases ◽  
Signaling Cascades ◽  
Contractile Element ◽  
Muscle Plasticity ◽  
Wide Range

Smooth muscles develop isometric force over a very wide range of cell lengths. The molecular mechanisms of this phenomenon are undefined, but are described as reflecting "mechanical plasticity" of smooth muscle cells. Plasticity is defined here as a persistent change in cell structure or function in response to a change in the environment. Important environmental stimuli that trigger muscle plasticity include chemical (e.g., neurotransmitters, autacoids, and cytokines) and external mechanical signals (e.g., applied stress and strain). Both kinds of signals are probably transduced by ionic and protein kinase signaling cascades to alter gene expression patterns and changes in the cytoskeleton and contractile system. Defining the signaling mechanisms and effector proteins mediating phenotypic and mechanical plasticity of smooth muscles is a major goal in muscle cell biology. Some of the signaling cascades likely to be important include calcium-dependent protein kinases, small GTPases (Rho, Rac, cdc42), Rho kinase, protein kinase C (PKC), Src family tyrosine kinases, mitogen-activated protein (MAP) kinases, and p21 activated protein kinases (PAK). There are many potential targets for these signaling cascades including nuclear processes, metabolic pathways, and structural components of the cytoskeleton. There is growing appreciation of the dynamic nature of the actin cytoskeleton in smooth muscles and the necessity for actin remodeling to occur during contraction. The actin cytoskeleton serves many functions that are probably critical for muscle plasticity including generation and transmission of force vectors, determination of cell shape, and assembly of signal transduction machinery. Evidence is presented showing that actin filaments are dynamic and that actin-associated proteins comprising the contractile element and actin attachment sites are necessary for smooth muscle contraction.Key words: integrin, muscle mechanics, paxillin, Rho, HSP27.

Superfamily I helicases as modular components of DNA-processing machines

2011 ◽  
Vol 39 (2) ◽  
pp. 413-423 ◽  
Author(s):  
Mark S. Dillingham
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Molecular Mechanisms ◽  
Acid Metabolism ◽  
Nucleic Acid Metabolism ◽  
Cellular Functions ◽  
Dna Helicases ◽  
Wide Range ◽  
Look Back ◽  
Partner Proteins

Helicases are a ubiquitous and abundant group of motor proteins that couple NTP binding and hydrolysis to processive unwinding of nucleic acids. By targeting this activity to a wide range of specific substrates, and by coupling it with other catalytic functionality, helicases fulfil diverse roles in virtually all aspects of nucleic acid metabolism. The present review takes a look back at our efforts to elucidate the molecular mechanisms of UvrD-like DNA helicases. Using these well-studied enzymes as examples, we also discuss how helicases are programmed by interactions with partner proteins to participate in specific cellular functions.

Role of O-Linked N-acetylglucosamine (O-GlcNAc) Protein Modification in Cellular (Patho)Physiology

2020 ◽  
Author(s):  
John C. Chatham ◽  
Jianhua Zhang ◽  
Adam Raymond Wende
Keyword(s):  
Chromatin Remodeling ◽  
Protein Modification ◽  
Protein Localization ◽  
Cellular Functions ◽  
Secretory Pathways ◽  
Cellular Physiology ◽  
Cytoplasmic Proteins ◽  
Wide Range ◽  
Glcnac Transferase

In the mid 1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by an O-linkage by a N-acetylglucosamine moiety (O-GlcNAc) overturned the widely held assumption that glycosylation only occurred in the endoplasmic reticulum, Golgi apparatus, and secretory pathways. In contrast to traditional glycosylation, the O-GlcNAc modification does not lead to complex branched glycan structures and is rapidly cycled on and off proteins by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Since its discovery O-GlcNAcylation has been shown to contribute to numerous cellular functions including signaling, protein localization and stability, transcription, chromatin remodeling, mitochondrial function, and cell survival. Dysregulation in O-GlcNAc cycling has been implicated in the progression of a wide range of diseases such as diabetes, diabetic complications, cancer, cardiovascular, and neurodegenerative diseases. This review will outline our current understanding of the processes involved in regulating O-GlcNAc turnover, the role of O-GlcNAcylation in regulating cellular physiology, and how dysregulation in O-GlcNAc cycling contributes to pathophysiological processes.

scholarly journals ERK1,2 Signalling Pathway along the Nephron and Its Role in Acid-base and Electrolytes Balance

2019 ◽  
Vol 20 (17) ◽  
pp. 4153 ◽  
Author(s):  
Giovanna Capolongo ◽  
Yoko Suzumoto ◽  
Mariavittoria D’Acierno ◽  
Mariadelina Simeoni ◽  
Giovambattista Capasso ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Mapk Signaling ◽  
Signalling Pathway ◽  
Renal Diseases ◽  
Cellular Functions ◽  
Acid Base ◽  
Mapk Activity ◽  
Extracellular Signal ◽  
Wide Range ◽  
Mitogen Activated Protein

Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.

scholarly journals Shiga Toxin 2 and Flagellin from Shiga-Toxigenic Escherichia coli Superinduce Interleukin-8 through Synergistic Effects on Host Stress-Activated Protein Kinase Activation

2010 ◽  
Vol 78 (7) ◽  
pp. 2984-2994 ◽  
Author(s):  
Dakshina M. Jandhyala ◽  
Trisha J. Rogers ◽  
Anne Kane ◽  
Adrienne W. Paton ◽  
James C. Paton ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protein Kinase ◽  
Protein Expression ◽  
Protein Kinases ◽  
Gene Transcription ◽  
Shiga Toxin ◽  
Systemic Circulation ◽  
Interleukin 8 ◽  
Intestinal Lumen ◽  
Chemokine Expression

ABSTRACT Shiga toxins expressed in the intestinal lumen during infection with Shiga-toxigenic Escherichia coli must translocate across the epithelium and enter the systemic circulation to cause systemic (pathological) effects, including hemolytic uremic syndrome. The transepithelial migration of polymorphonuclear leukocytes in response to chemokine expression by intestinal epithelial cells is thought to promote uptake of Stx from the intestinal lumen by compromising the epithelial barrier. In the present study, we investigated the hypothesis that flagellin acts in conjunction with Shiga toxin to augment this chemokine expression. We investigated the relative contributions of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling to transcription and translation of interleukin-8. Using reporter gene constructs, we showed that flagellin-mediated interleukin-8 gene transcription is heavily dependent on both NF-κB and extracellular signal-regulated kinase 1 and 2 (ERK-1/2) activation. In contrast, inhibition of p38 has no detectable effect on interleukin-8 gene transcription, even though flagellin-mediated activation of host p38 is critical for maximal interleukin-8 protein expression. Inhibition of MAPK-interacting kinase 1 suggests that p38 signaling affects the posttranscriptional regulation of interleukin-8 protein expression induced by flagellin. Cotreatment with Stx2 and flagellin results in a synergistic upregulation of c-Jun N-terminal protein kinases (JNKs), p38 activation, and a superinduction of interleukin-8 mRNA. This synergism was also evident at the protein level, with increased interleukin-8 protein detectable following cotreatment with flagellin and Stx2. We propose that flagellin, in conjunction with Shiga toxin, synergistically upregulates stress-activated protein kinases, resulting in superinduction of interleukin-8 and, ultimately, absorption of Stx into the systemic circulation.

scholarly journals Functions and regulation of the serine/threonine protein kinase CK1 family: moving beyond promiscuity

2020 ◽  
Vol 477 (23) ◽  
pp. 4603-4621
Author(s):  
Luke J. Fulcher ◽  
Gopal P. Sapkota
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Therapeutic Targets ◽  
Signalling Pathways ◽  
Biological Processes ◽  
Cellular Functions ◽  
Intracellular Regulation ◽  
Constitutively Active

Regarded as constitutively active enzymes, known to participate in many, diverse biological processes, the intracellular regulation bestowed on the CK1 family of serine/threonine protein kinases is critically important, yet poorly understood. Here, we provide an overview of the known CK1-dependent cellular functions and review the emerging roles of CK1-regulating proteins in these processes. We go on to discuss the advances, limitations and pitfalls that CK1 researchers encounter when attempting to define relationships between CK1 isoforms and their substrates, and the challenges associated with ascertaining the correct physiological CK1 isoform for the substrate of interest. With increasing interest in CK1 isoforms as therapeutic targets, methods of selectively inhibiting CK1 isoform-specific processes is warranted, yet challenging to achieve given their participation in such a vast plethora of signalling pathways. Here, we discuss how one might shut down CK1-specific processes, without impacting other aspects of CK1 biology.

Much to know about proteolysis: intricate proteolytic machineries compromise essential cellular functions

2008 ◽  
Vol 36 (5) ◽  
pp. 781-785 ◽  
Author(s):  
Gemma Marfany ◽  
Rosa Farràs ◽  
Eduardo Salido ◽  
Dimitris P. Xirodimas ◽  
Manuel S. Rodríguez
Keyword(s):  
Protein Complexes ◽  
Ubiquitin Proteasome System ◽  
Cellular Functions ◽  
Cell Functions ◽  
Starting Point ◽  
Wide Range ◽  
Cellular Factors ◽  
Ubiquitin Proteasome ◽  
The University ◽  
Intracellular Proteolysis

Proteolysis has traditionally been considered as a radical way to terminate the function of a protein. However, protein destruction also is the starting point for many processes as they can only occur when the way has been cleared for the action of other proteins. Protein destruction can occur virtually in all compartments and organelles of the cell, associated with cell membranes or large protein complexes, it determines subcellular partitioning, association with positive or negative regulators which conditions the action of many critical cellular factors. The third intracellular proteolysis meeting held by the University La Laguna, Canary Islands, Spain, included speakers working with some of the most important proteolytic systems present in higher eukaryotes, such as the UPS (ubiquitin–proteasome system) and autophagy. Owing to the fact that these pathways directly or indirectly regulate many cell functions, this meeting brought together an audience with a wide range of research interests, including genetic, cell biological, biochemical and structural aspects of protein degradation. Some of these topics inspired interesting discussions and a significant number of these are developed in the issues reviewed herein.

scholarly journals Phosphatidylinositol-3,4,5-Triphosphate and Cellular Signaling: Implications for Obesity and Diabetes

2015 ◽  
Vol 35 (4) ◽  
pp. 1253-1275 ◽  
Author(s):  
Prasenjit Manna ◽  
Sushil K. Jain
Keyword(s):  
Metabolic Diseases ◽  
Specific Binding ◽  
Cell Metabolism ◽  
Effector Proteins ◽  
Current Status ◽  
Cellular Functions ◽  
Binding Domains ◽  
Obesity And Diabetes ◽  
Impaired Metabolism ◽  
Wide Range

Phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) is one of the most important phosphoinositides and is capable of activating a wide range of proteins through its interaction with their specific binding domains. Localization and activation of these effector proteins regulate a number of cellular functions, including cell survival, proliferation, cytoskeletal rearrangement, intracellular vesicle trafficking, and cell metabolism. Phosphoinositides have been investigated as an important agonist-dependent second messenger in the regulation of diverse physiological events depending upon the phosphorylation status of their inositol group. Dysregulation in formation as well as metabolism of phosphoinositides is associated with various pathophysiological disorders such as inflammation, allergy, cardiovascular diseases, cancer, and metabolic diseases. Recent studies have demonstrated that the impaired metabolism of PtdIns(3,4,5)P3 is a prime mediator of insulin resistance associated with various metabolic diseases including obesity and diabetes. This review examines the current status of the role of PtdIns(3,4,5)P3 signaling in the regulation of various cellular functions and the implications of dysregulated PtdIns(3,4,5)P3 signaling in obesity, diabetes, and their associated complications.

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