Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both rapidly broken down to salicylate in vivo. At concentrations reached in plasma following administration of salsalate, or aspirin at high doses, salicylate activates ...

Axl is a receptor tyrosine kinase that was originally cloned from cancer cells. Axl belongs to the TAM (Tyro3, Axl and Mertk) family of receptor tyrosine kinases. Gas6 (growth-arrest-specific protein 6) is a ligand for Axl. Activation of Axl protects cells from apoptosis, and increases migration, aggregation and growth through ...

The transcription factor Twist plays vital roles during embryonic development through regulating/controlling cell migration. However, postnatally, in normal physiological settings, Twist is either not expressed or inactivated. Increasing evidence shows a strong correlation between Twist reactivation and both cancer progression and malignancy, where the transcriptional activities of Twist support cancer ...

The MKPs (mitogen-activated protein kinase phosphatases) are a family of at least ten DUSPs (dual-specificity phosphatases) which function to terminate the activity of the MAPKs (mitogen-activated protein kinases). Several members have already been demonstrated to have distinct roles in immune function, cancer, fetal development and metabolic disorders. One DUSP of ...

Proteasome inhibition is a promising approach for cancer treatment; however, the underlying mechanisms involved have not been fully elucidated. Here, we show that proteasome inhibition-induced p38 mitogen-activated protein kinase regulates autophagy and apoptosis by modulating the phosphorylation status of glycogen synthase kinase 3β (GSK3β) and 70kDa ribosomal S6 kinase (p70S6K). ...

For more than 60 years, the mood stabilizer lithium has been used alone or in combination for the treatment of bipolar disorder, schizophrenia, depression, and other mental illnesses. Despite this long history, the molecular mechanisms trough which lithium regulates behavior are still poorly understood. Among several targets, lithium has been ...

Programmed necrosis has long been recognized as a crucial component of animal development; however, the signaling pathway beyond the protein kinases RIP1 and RIP3 remains largely unknown. Sun et al. and Wang et al. now identify critical factors downstream of RIP1 and RIP3 in programmed necrosis, extending our understanding of this form ...

The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide--hereafter referred ...

Studies on the regulation of cellular activity mainly focus on signal generation, but termination of the signaling is an equally important factor, which prevents inappropriate activity. This paper reviews the mechanisms, which can cause termination of signaling, and provides examples that illustrate the importance of these processes. Inactivation of voltage-gated ...

The RSK (90 kDa ribosomal S6 kinase) family comprises a group of highly related serine/threonine kinases that regulate diverse cellular processes, including cell growth, proliferation, survival and motility. This family includes four vertebrate isoforms (RSK1, RSK2, RSK3 and RSK4), and single family member orthologues are also present in Drosophila and Caenorhabditis ...

In metazoans, TOR is an essential protein that functions as a master regulator of cellular growth and proliferation. Over the past decade, there has been an explosion of information about this critical master kinase, ranging from the composition of the TOR protein complex to its ability to act as an ...

The knowledge of molecular control mechanisms underlying the basal tone in the intact human IAS is critical for the pathophysiology and rational therapy for a number of debilitating rectoanal motility disorders. We determined the role of RhoA/ROCK and PKC pathways by comparing the effects of ROCK and PKC-selective inhibitors Y ...

PURPOSE OF REVIEW: This review summarizes the recent advances in molecular mechanisms by which five classes of receptor tyrosine kinases (RTKs) contribute to vascular remodeling. RECENT FINDINGS: Recent findings have expanded our knowledge regarding RTK regulation. In particular, G-protein-coupled receptors, mineralocorticoid receptors, mechanical and oxidative stresses transactivate RTKs. These receptors ...

Covering: up to 2001Natural products have been widely used to dissect the basic mechanisms of fundamental life science and as clinical therapeutics. Recently, there has been significant interest in discovering new chemical pharmacophores in natural products to fulfil the vast demand for novel kinase inhibitors and address critical unmet medical ...

Protein kinase inhibitors have emerged as indispensable tools for the elucidation of the biological functions of specific signal transduction pathways and as promising candidates for molecular-targeted therapy. However, because many protein kinase inhibitors are ATP-competitive inhibitors targeting the catalytic site of specific protein kinases, the large number of protein kinases ...

The mammalian (or mechanistic) target of rapamycin (mTOR) is an evolutionarily conserved serine-threonine kinase that is known to sense the environmental and cellular nutrition and energy status. Diverse mitogens, growth factors, and nutrients stimulate the activation of the two mTOR complexes mTORC1 and mTORC2 to regulate diverse functions, such as ...

The mammalian Target Of Rapamycin (mTOR) protein is a central component of the essential and highly conserved signaling pathway that emerged as a critical effector in regulation of cell physiology. Biochemical studies defined mTOR as the protein kinase that exists at least in two distinct complexes. The first complex has ...

The mammalian Target of Rapamycin (mTOR) kinase functions within two structurally and functionally distinct multiprotein complexes termed mTOR complex 1 (mTORC1) and mTORC2. The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study mTOR signaling. However, rapamycin inhibits only, and only incompletely, mTORC1, ...

In 1985, the first members of the Rho GTPase family were identified. Over the next 10 years, rapid progress was made in understanding Rho GTPase signalling. Multiple Rho GTPases were discovered in a wide range of eukaryotes, and shown to regulate a diverse range of cellular processes, including cytoskeletal dynamics, ...

We study signaling cascades with an arbitrary number of layers of one-site phosphorylation cycles. Such cascades are abundant in nature and integrated parts of many pathways. Based on the Michaelis-Menten model of enzyme kinetics and the law of mass-action, we derive explicit analytic expressions for how the steady state concentrations ...

The p85α protein is best known as the regulatory subunit of class 1A PI3Ks (phosphoinositide 3-kinases) through its interaction, stabilization and repression of p110-PI3K catalytic subunits. PI3Ks play multiple roles in the regulation of cell survival, signalling, proliferation, migration and vesicle trafficking. The present review will focus on p85α, with ...

It is now well established that G-protein coupled receptors (GPCRs) are hyper-phosphorylated following agonist occupation usually at serine and threonine residues contained on the third intracellular loop and C-terminal tail. After some 2 decades of intensive research, the nature of protein kinases involved in this process together with the signalling ...

Living cells respond to various environmental cues and process them into a series of spatially and temporally regulated signaling events, which can be tracked in real time with an expanding repertoire of genetically encodable FRET-based biosensors. A series of these biosensors, designed to track dynamic activities of signaling enzymes such ...

The canonical Wnt signaling pathway is critical for development of the mammalian central nervous system and regulates diverse processes throughout adulthood, including adult neurogenesis. Glycogen synthase kinase-3 (GSK-3) antagonizes the canonical Wnt pathway and therefore also plays a central role in neural development and adult neurogenesis. Lithium, the first line ...

Ligands of the Transforming Growth Factor β superfamily like Transforming Growth Factor β and Bone Morphogenetic Proteins govern developmental processes and regulate adult homeostasis by controlling cellular proliferation, survival, differentiation and migration. Aberrant signalling activity is associated with human disorders such as cancer, cardiovascular, musculoskeletal, or fibrotic disease. Upon binding ...

Chemical space is defined as all possible small organic molecules, including those present in biological systems, which is so vast that so far only a tiny fraction of it has been explored. Indeed, a thorough examination of all "chemical space" is practically impossible. The success of three EGFR inhibitors (Gefitnib, ...

Until now, a lack of inhibitors with high potency and selectivity in vivo has hampered investigation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We describe the design of skepinone-L, which is, to our knowledge, the first ATP-competitive p38 MAPK inhibitor with excellent in vivo efficacy and selectivity. Therefore, ...

Dupuytren's disease (DD) is a benign progressive fibro-proliferative disorder of the fascia palmaris of the hand. Currently, treatment consists of surgical excision with a relatively high recurrence rate and risk of complications. To improve long-term outcome of DD treatment, research focus has shifted towards molecular targets for DD as an ...

Protein kinase D1 (PKD1) is a stress-activated serine/threonine kinase that plays a vital role in various physiologically important biological processes, including cell growth, apoptosis, adhesion, motility, and angiogenesis. Dysregulated PKD1 expression also contributes to the pathogenesis of certain cancers and cardiovascular disorders. Studies to date have focused primarily on the ...

After the discovery of molecules modulating G protein-coupled receptors (GPCRs) that are able to selectively affect one signaling pathway over others for a specific GPCR, thereby "biasing" the signaling, it has become obvious that the original model of GPCRs existing in either an "on" or "off" conformation is too simple. ...

Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in ...

Nuclear factor-κB (NF-κB) is a master regulator of immunity and also involved in malignant transformation. It has been widely accepted that Lys-48 (K48)-linked polyubiquitination plays a critical role in NF-κB signaling by targeting inhibitor of NF-κB (IκB), thereby leading to its degradation by the proteasome. Alternatively, studies on IL-1 and ...

Mitogen-activated protein kinases (MAPKs) are key regulators of cellular physiology and immune responses and abnormality in MAPKs is implicated in many diseases. MAPKs are activated by MAPK kinases through phosphorylation of the threonine and tyrosine residues in the conserved Thr-Xaa-Tyr domain, where Xaa represents amino acid residues characteristic of distinct ...

Over the past few decades, our understanding of the embryonic gene Cripto-1 has considerably advanced through biochemical, cell biology, and animal studies. Cripto-1 performs key functions during embryonic development, while it dramatically disappears in adult tissues, except possibly in adult tissue stem cells. Cripto-1 is re-expressed in human tumors promoting ...

This year (2012) marks the 50th anniversary of the discovery of protein histidine phosphorylation. Phosphorylation of histidine (pHis) is now widely recognized as being critical to signaling processes in prokaryotes and lower eukaryotes. However, the modification is also becoming more widely reported in mammalian cellular processes and implicated in certain ...

Amongst different posttranslational events involved in cellular-signaling pathways, phosphorylation and dephosphorylation of proteins are the most prevalent. Aberrant regulations in the cellular phosphoproteome network are implicated in most major human diseases. Consequently, kinases and phosphatases are two of the most important groups of drug targets in medicinal research today. A ...

The mammalian CIP/KIP family of cyclin-dependent kinase (CDK) inhibitors (CKIs) comprises three proteins--p21(Cip1/WAF1), p27(Kip1), and p57(Kip2)--that bind and inhibit cyclin-CDK complexes, which are key regulators of the cell cycle. CIP/KIP CKIs have additional independent functions in regulating transcription, apoptosis and actin cytoskeletal dynamics. These divergent functions are performed in distinct ...

Reproduction is a critical element of life. Self-propagation in all living organisms ranging from bacteria to humans involves numerous common strategies. Underlying all reproductive strategies is the essential need for signaling molecules to initiate and maintain the process. In this paper we use comparative biological and chemical approaches to explore ...

Vascular endothelial growth factor Receptor-2 (VEGFR-2) kinase inhibition is one of the well established strategies to promptly tackle tumor growth by suppression of angiogenesis. In the current study, structure-based virtual screening methodology of a series of quinolyl-thienyl chalcones indicated their strong potential as VEGFR-2 kinase inhibitors. In vitro VEGFR-2 kinase ...

Understanding the molecular and cellular mechanisms involved in the progression of atherosclerosis has revealed a vital role for the Rho kinase (ROCK) pathway associated with stiffening of the underlying extracellular matrix (Huynh et al., this issue).

The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is the prototype mammalian mitogen-activated protein kinase (MAPK) signaling cascade that regulates a number of processes, including proliferation, differentiation, survival, migration, stress responses and apoptosis. How this seemingly linear cascade is modulated to achieve a specific cellular function has been a main focus ...

Genetic and biochemical studies have defined the Hippo pathway as a central mediator of developmental and pathogenic signals. By directing intracellular signaling events, the Hippo pathway fine-tunes cell proliferation, cell death, and cell-fate decisions, and coordinates these cues to specify animal organ size. Recent studies have revealed that Hippo pathway-mediated ...

Essential roles of NRP1 (neuropilin-1) in cardiovascular development and in neuronal axon targeting during embryogenesis are thought to be mediated primarily through binding of NRP1 to two unrelated types of ligands: the VEGF (vascular endothelial growth factor) family of angiogenic cytokines in the endothelium, and the class 3 semaphorins in ...

Tissue and organ transplantation constitute the main medical advances of the last century, and has been possible thanks to the contribution of doctors like Loix Roux, who, in 1885, firstly described a technique consisting on tissue culture ex vivo, or Emerich Ullman and Max Lederer, whose publications in 1914 collected ...

Here we describe a method for the engineered regulation of protein kinases in living cells, the design and application of RapR (rapamycin regulated) kinases. The RapR kinase method enables activation of kinases with high specificity and precise temporal control. Insertion of an engineered allosteric switch, the iFKBP domain, at a ...

TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin ...

The mammalian p38 mitogen-activated protein kinases (MAPKs) family is composed of four members (p38α, p38β, p38γ, and p38δ), which are very similar in amino acid sequence but differ in their expression patterns. This suggests that they may have specific functions in different organs. In the last years most of the ...

ADF/cofilins are the major regulators of actin dynamics in mammalian cells. The activation of ADF/cofilins is controlled by a variety of regulatory mechanisms. Dysregulation of ADF/cofilin may result in loss of a precisely organized actin cytoskeletal architecture and can reduce podocyte migration and motility. Recent studies suggest that cofilin-1 can ...

A-kinase anchoring proteins (AKAPs) crucially contribute to the spatial and temporal control of cellular signalling. They directly interact with a variety of protein binding partners and cellular constituents thereby directing pools of signalling components to defined locales. In particular, AKAPs mediate compartmentalisation of cAMP signalling. Alterations in AKAP expression and ...

Although PI3K/Akt signaling that regulates neuronal survival has been implicated in the deleterious effects of ethanol on the central nervous system, underlying molecular mechanisms have not been fully elucidated. Akt-membrane interaction is a prerequisite step for Akt activation since it induces inter-domain conformational changes to an open conformer that allows ...