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.

The Sucrose Non-Fermenting 1-Related Protein Kinase 2 (SnRK2) Genes Are Multifaceted Players in Plant Growth, Development and Response to Environmental Stimuli

2019 ◽  
Vol 61 (2) ◽  
pp. 225-242 ◽  
Author(s):  
Xinguo Mao ◽  
Yuying Li ◽  
Shoaib Ur Rehman ◽  
Lili Miao ◽  
Yanfei Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Specific Protein ◽  
Regulatory Mechanisms ◽  
Biological Processes ◽  
Related Protein ◽  
Biological Functions ◽  
Reversible Protein Phosphorylation ◽  
Growth Development ◽  
Regulatory Event

Abstract Reversible protein phosphorylation orchestrated by protein kinases and phosphatases is a major regulatory event in plants and animals. The SnRK2 subfamily consists of plant-specific protein kinases in the Ser/Thr protein kinase superfamily. Early observations indicated that SnRK2s are mainly involved in response to abiotic stress. Recent evidence shows that SnRK2s are multifarious players in a variety of biological processes. Here, we summarize the considerable knowledge of SnRK2s, including evolution, classification, biological functions and regulatory mechanisms at the epigenetic, post-transcriptional and post-translation levels.

Snf1-related protein kinases (SnRKs) act within an intricate network that links metabolic and stress signalling in plants

2009 ◽  
Vol 419 (2) ◽  
pp. 247-259 ◽  
Author(s):  
Nigel G. Halford ◽  
Sandra J. Hey
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Signalling Pathways ◽  
Related Protein ◽  
Major Mechanism ◽  
Intracellular Signals ◽  
Kinase Cascade ◽  
Eukaryotic Organisms ◽  
Amp Activated Protein Kinase ◽  
Stress Signalling

The phosphorylation and dephosphorylation of proteins, catalysed by protein kinases and phosphatases, is the major mechanism for the transduction of intracellular signals in eukaryotic organisms. Signalling pathways often comprise multiple phosphorylation/dephosphorylation steps and a long-standing hypothesis to explain this phenomenon is that of the protein kinase cascade, in which a signal is amplified as it is passed from one step in a pathway to the next. This review represents a re-evaluation of this hypothesis, using the signalling network in which the SnRKs [Snf1 (sucrose non-fermenting-1)-related protein kinases] function as an example, but drawing also on the related signalling systems involving Snf1 itself in fungi and AMPK (AMP-activated protein kinase) in animals. In plants, the SnRK family comprises not only SnRK1, but also two other subfamilies, SnRK2 and SnRK3, with a total of 38 members in the model plant Arabidopsis. This may have occurred to enable linking of metabolic and stress signalling. It is concluded that signalling pathways comprise multiple levels not to allow for signal amplification, but to enable linking between pathways to form networks in which key protein kinases, phosphatases and target transcription factors represent hubs on/from which multiple pathways converge and emerge.

scholarly journals Diversity, classification and function of the plant protein kinase superfamily

2012 ◽  
Vol 367 (1602) ◽  
pp. 2619-2639 ◽  
Author(s):  
Melissa D. Lehti-Shiu ◽  
Shin-Han Shiu
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Plant Protein ◽  
Flowering Plant ◽  
Cellular Functions ◽  
Functional Protein ◽  
Low Copy Number ◽  
Receptor Like Kinase ◽  
Insufficient Time ◽  
And Function

Eukaryotic protein kinases belong to a large superfamily with hundreds to thousands of copies and are components of essentially all cellular functions. The goals of this study are to classify protein kinases from 25 plant species and to assess their evolutionary history in conjunction with consideration of their molecular functions. The protein kinase superfamily has expanded in the flowering plant lineage, in part through recent duplications. As a result, the flowering plant protein kinase repertoire, or kinome, is in general significantly larger than other eukaryotes, ranging in size from 600 to 2500 members. This large variation in kinome size is mainly due to the expansion and contraction of a few families, particularly the receptor-like kinase/Pelle family. A number of protein kinases reside in highly conserved, low copy number families and often play broadly conserved regulatory roles in metabolism and cell division, although functions of plant homologues have often diverged from their metazoan counterparts. Members of expanded plant kinase families often have roles in plant-specific processes and some may have contributed to adaptive evolution. Nonetheless, non-adaptive explanations, such as kinase duplicate subfunctionalization and insufficient time for pseudogenization, may also contribute to the large number of seemingly functional protein kinases in plants.

scholarly journals Kinase-interacting substrate screening is a novel method to identify kinase substrates

2015 ◽  
Vol 209 (6) ◽  
pp. 895-912 ◽  
Author(s):  
Mutsuki Amano ◽  
Tomonari Hamaguchi ◽  
Md. Hasanuzzaman Shohag ◽  
Kei Kozawa ◽  
Katsuhiro Kato ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Ternary Complex ◽  
Rho Kinase ◽  
Phosphorylation Sites ◽  
Dependent Manner ◽  
Cellular Functions ◽  
Associated Proteins ◽  
Novel Method ◽  
Kinase Substrates

Protein kinases play pivotal roles in numerous cellular functions; however, the specific substrates of each protein kinase have not been fully elucidated. We have developed a novel method called kinase-interacting substrate screening (KISS). Using this method, 356 phosphorylation sites of 140 proteins were identified as candidate substrates for Rho-associated kinase (Rho-kinase/ROCK2), including known substrates. The KISS method was also applied to additional kinases, including PKA, MAPK1, CDK5, CaMK1, PAK7, PKN, LYN, and FYN, and a lot of candidate substrates and their phosphorylation sites were determined, most of which have not been reported previously. Among the candidate substrates for Rho-kinase, several functional clusters were identified, including the polarity-associated proteins, such as Scrib. We found that Scrib plays a crucial role in the regulation of subcellular contractility by assembling into a ternary complex with Rho-kinase and Shroom2 in a phosphorylation-dependent manner. We propose that the KISS method is a comprehensive and useful substrate screen for various kinases.

scholarly journals Protein kinase signalling at the Leishmania kinetochore captured by XL-BioID

2021 ◽  
Author(s):  
Vincent Geoghegan ◽  
Nathaniel G. Jones ◽  
Adam Dowle ◽  
Jeremy C Mottram
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Cell Biology ◽  
Specific Inhibitor ◽  
Signalling Pathways ◽  
Kinetochore Protein ◽  
Protein Kinase Inhibition ◽  
Protein Kinase Signaling ◽  
Protein Kinase Signalling

Elucidating protein kinase signaling pathways is an important but challenging problem in cell biology. Phosphoproteomics has been used to identify many phosphorylation sites, however the spatial context of these sites within the cell is mostly unknown, making it difficult to reconstruct signalling pathways. To address this problem an in vivo proximity capturing workflow was developed, consisting of proximity biotinylation followed by protein cross-linking (XL-BioID). This was applied to protein kinases of the Leishmania kinetochore, leading to the discovery of a novel essential kinetochore protein, KKT26. XL-BioID enabled the quantification of proximal phosphosites at the kinetochore through the cell cycle, allowing the phosphorylation state of the kinetochore to be followed during assembly. A specific inhibitor of kinetochore protein kinases KKT10/KKT19 was used to show that XL-BioID provides a spatially focussed view of protein kinase inhibition, identifying 16 inhibitor-responsive proximal phosphosites, including 3 on KKT2, demonstrating the potential of this approach for discovery of in vivo kinase signalling pathways.

Historical perspectives on protein phosphorylation and a classification system for protein kinases

1983 ◽  
Vol 302 (1108) ◽  
pp. 3-11 ◽  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Protein Kinases ◽  
Major Type ◽  
Biological Processes ◽  
Dependent Protein Kinase ◽  
Allosteric Control ◽  
Historical Perspectives ◽  
Phosphorylation Of Proteins ◽  
Dependent Protein

Work on the phosphorylation of proteins as a dynamic process involved in the regulation of biological processes started in the 1950s with the finding that phosphorylase a and phosphorylase b are phospho and dephospho forms of the same enzyme. The field expanded sharply in the late 1960s with the discovery of the cyclic-AMP-dependent protein kinase, and it is now clear that phosphorylation-dephosphorylation constitutes a major type of regulation almost as common as allosteric control. The protein kinases, which catalyse the phosphorylation step in various phosphorylationdephosphorylation systems, can be divided into two main classes, the serine-threonine protein kinases and the tyrosine protein kinases. Each class can be subdivided into groups or entities depending on the nature of the agent(s) that regulate activity.

scholarly journals Angiotensin II-Mediated Protein Kinase D Activation Stimulates Aldosterone and Cortisol Secretion in H295R Human Adrenocortical Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 6046-6055 ◽  
Author(s):  
Damian G. Romero ◽  
Bronwyn L. Welsh ◽  
Elise P. Gomez-Sanchez ◽  
Licy L. Yanes ◽  
Silvia Rilli ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Protein Kinase D ◽  
Cell Physiology ◽  
Cortisol Secretion ◽  
Adrenal Cells ◽  
Constitutively Active

Protein kinases are important mediators in intracellular signaling. Angiotensin II is the most important modulator of adrenal zona glomerulosa cell physiology. Angiotensin II regulates steroidogenesis and proliferation among many other metabolic processes. H295R human adrenal cells are a widely used experimental model to study adrenal cell physiology and metabolism. We screened for protein kinase expression levels using the Kinetwork system in H295R cells after 3 h angiotensin II treatment. Protein kinase D (PKD) was the protein kinase that suffers the most dramatic changes. PKD is a member of a new class of serine/threonine protein kinases that is activated by phosphorylation. Our studies indicated that angiotensin II time- and dose-dependently increased PKD phosphorylation, which occurred within 2 min of angiotensin II treatment and at concentrations as low as 1 nm. PKD phosphorylation was also dose-dependently increased by the PKC activator phorbol 12-myristate 13-acetate. Angiotensin II-mediated PKD phosphorylation was blocked by several PKC inhibitors. Furthermore, PKCε translocation inhibitor peptide decreased angiotensin II-mediated PKD phosphorylation, and PKCε down-regulation by RNA interference also decreased PKD phosphorylation mediated by angiotensin II. Cotransfection of constitutively active PKD mutant constructs up-regulated aldosterone synthase and 11β-hydroxylase expression in reporter assays. Constitutively active PKD mutants increased aldosterone and cortisol secretion under angiotensin II stimulatory conditions. This study reveals that PKD is an intracellular signaling mediator of angiotensin II regulation of steroidogenesis in human adrenal cells. These data provide new insights into the molecular mechanisms involved in angiotensin II-induced physiological and pathophysiological events in adrenal cells.

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.

Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1

2010 ◽  
Vol 433 (2) ◽  
pp. 357-369 ◽  
Author(s):  
Ayaz Najafov ◽  
Eeva M. Sommer ◽  
Jeffrey M. Axten ◽  
M. Phillip Deyoung ◽  
Dario R. Alessi
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Embryonic Stem ◽  
Specific Inhibitor ◽  
Prolonged Treatment ◽  
Pleckstrin Homology Domain ◽  
Biological Processes ◽  
S6 Kinase ◽  
Ribosomal S6 Kinase ◽  
Kinase Pathway

PDK1 (3-phosphoinositide-dependent protein kinase 1) activates a group of protein kinases belonging to the AGC [PKA (protein kinase A)/PKG (protein kinase G)/PKC (protein kinase C)]-kinase family that play important roles in mediating diverse biological processes. Many cancer-driving mutations induce activation of PDK1 targets including Akt, S6K (p70 ribosomal S6 kinase) and SGK (serum- and glucocorticoid-induced protein kinase). In the present paper, we describe the small molecule GSK2334470, which inhibits PDK1 with an IC50 of ~10 nM, but does not suppress the activity of 93 other protein kinases including 13 AGC-kinases most related to PDK1 at 500-fold higher concentrations. Addition of GSK2334470 to HEK (human embryonic kidney)-293, U87 or MEF (mouse embryonic fibroblast) cells ablated T-loop residue phosphorylation and activation of SGK isoforms and S6K1 induced by serum or IGF1 (insulin-like growth factor 1). GSK2334470 also inhibited T-loop phosphorylation and activation of Akt, but was more efficient at inhibiting Akt in response to stimuli such as serum that activated the PI3K (phosphoinositide 3-kinase) pathway weakly. GSK2334470 inhibited activation of an Akt1 mutant lacking the PH domain (pleckstrin homology domain) more potently than full-length Akt1, suggesting that GSK2334470 is more effective at inhibiting PDK1 substrates that are activated in the cytosol rather than at the plasma membrane. Consistent with this, GSK2334470 inhibited Akt activation in knock-in embryonic stem cells expressing a mutant of PDK1 that is unable to interact with phosphoinositides more potently than in wild-type cells. GSK2334470 also suppressed T-loop phosphorylation and activation of RSK2 (p90 ribosomal S6 kinase 2), another PDK1 target activated by the ERK (extracellular-signal-regulated kinase) pathway. However, prolonged treatment of cells with inhibitor was required to observe inhibition of RSK2, indicating that PDK1 substrates possess distinct T-loop dephosphorylation kinetics. Our data define how PDK1 inhibitors affect AGC signalling pathways and suggest that GSK2334470 will be a useful tool for delineating the roles of PDK1 in biological processes.

scholarly journals Activation of the extracellular signal-regulated kinase by complement C5b-9

2005 ◽  
Vol 289 (3) ◽  
pp. F593-F603 ◽  
Author(s):  
Andrey V. Cybulsky ◽  
Tomoko Takano ◽  
Joan Papillon ◽  
Krikor Bijian ◽  
Julie Guillemette
Keyword(s):  
Protein Kinase ◽  
Actin Cytoskeleton ◽  
Protein Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Glomerular Epithelial Cell ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Constitutively Active

Extracellular signals may be transmitted to nuclear or cytoplasmic effectors via the mitogen-activated protein kinases. In the passive Heymann nephritis (PHN) model of membranous nephropathy, complement C5b-9 induces glomerular epithelial cell (GEC) injury, proteinuria, and activation of phospholipases and protein kinases. This study addresses the complement-mediated activation of the extracellular signal-regulated kinase (ERK). C5b-9 induced ERK threonine202/tyrosine204 phosphorylation (which correlates with activation) in GEC in culture and PHN in vivo. Expression of a dominant-inhibitory mutant of Ras reduced complement-mediated activation of ERK, but activation was not affected significantly by downregulation of protein kinase C. Complement-induced ERK activation resulted in phosphorylation of cytosolic phospholipase A2 and was, in part, responsible for phosphorylation of mitogen-activated protein kinase-associated protein kinase-2, but did not induce phosphorylation of the transcription factor, Elk-1. Activation of ERK was attenuated by drugs that disassemble the actin cytoskeleton (cytochalasin D, latrunculin B), and these compounds interfered with the activation of ERK by mitogen-activated protein kinase kinase (MEK). Overexpression of a constitutively active RhoA as well as inhibition of Rho-associated kinase blocked complement-mediated ERK activation. Complement cytotoxicity was enhanced after disassembly of the actin cytoskeleton but was unaffected after inhibition of complement-induced ERK activation. However, complement cytotoxicity was enhanced in GEC that stably express constitutively active MEK. Thus complement-induced ERK activation depends on cytoskeletal remodelling and affects the regulation of distinct downstream substrates, while chronic, constitutive ERK activation exacerbates complement-mediated GEC injury.

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