Membrane proteins possess certain features that make them susceptible to the electric fields generated at the level of the plasma membrane. A reappraisal of cell signalling, taking into account the protein interactions with the membrane electrostatic profile, suggests that an electrical dimension is deeply involved in this fundamental aspect of cell biology. At least three types of potentials can contribute to this dimension: (1) the potential across the compact layer of water adherent to membrane surfaces; this potential is (...) affected by classical inducers of cell differentiation, like dimethylsulfoxide and hexamethylenebisacetamide; (2) the potential across the Gouy‐Chapman double layer, which accounts for the effects of extracellular cations in the modulation of differentiation; and (3) the resting potential. This last potential and its governing ion currents can be exploited in localised mechanisms of cell signalling centred on the functional association of integrin receptors with ion channels. (shrink)

Phosphatidylinositol 3‐phosphate (PtdIns3P) is generated on the cytosolic leaflet of cellular membranes, primarily by phosphorylation of phosphatidylinositol by class II and class III phosphatidylinositol 3‐kinases. The bulk of this lipid is found on the limiting and intraluminal membranes of endosomes, but it can also be detected in domains of phagosomes, autophagosome precursors, cytokinetic bridges, the plasma membrane and the nucleus. PtdIns3P controls cellular functions through recruitment of specific protein effectors, many of which contain FYVE or PX domains. Cellular processes known (...) to be controlled by PtdIns3P and its effectors include endosomal fusion, sorting and motility, autophagy, cytokinesis, regulated exocytosis and signal transduction. Here we discuss how Ptdins3P is generated on specific cellular membranes, how its localizations and functions can be studied, and how its effectors serve to control cellular functions.Editor's suggested further reading in BioEssays:Phosphatidylinositol 4,5‐bisphosphate: Targeted production and signalingAbstractHow does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity?AbstractPhosphatidylinositol‐3,4,5‐trisphosphate: Tool of choice for class I PI 3‐kinasesAbstractPhosphatidylinositol‐4‐phosphate: The Golgi and beyondAbstract. (shrink)

Intermediate filament (IF) proteins form the largest family of cytoskeletal proteins in mammalian cells. The function of these proteins has long been thought to be only structural. However, this single function does not explain their diverse tissue‐ and differentiation‐specific expression patterns. Evidence is now emerging that IF also act as an important framework for the modulation and control of essential cell processes, in particular, signal transduction events. Here, we review the most recent developments in this growing and exciting new (...) field. BioEssays 24:836–844, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The orderly sequence of events that constitutes the cell cycle is carefully regulated. A part of this regulation depends upon the ubiquitous calcium signalling system. Many growth factors utilize the messenger inositol trisphosphate (InsP3) to set up prolonged calcium signals, often organized in an oscillatory pattern. These repetitive calcium spikes require both the entry of external calcium and its release from internal stores. One function of this calcium signal is to activate the immediate early genes responsible for inducing resting (...) cells (G0) to re‐enter the cell cycle. It may also promote the initiation of DNA synthesis at the G1/S transition. Finally, calcium contributes to the completion of the cell cycle by stimulating events at mitosis. The role of calcium in cell proliferation is highlighted by the increasing number of anticancer therapies and immunosuppressant drugs directed towards this calcium signalling pathway. (shrink)

MUC1 and MUC4 are the two membrane mucins that have been best characterized. Although they have superficially similar structures and have both been shown to provide steric protection of epithelial surfaces, recent studies have also implicated them in cellular signaling. They act by substantially different mechanisms, MUC4 as a receptor ligand and MUC1 as a docking protein for signaling molecules. MUC4 is a novel intramembrane ligand for the receptor tyrosine kinase ErbB2/HER2/Neu, triggering a specific phosphorylation of the ErbB2 (...) in the absence of other ErbB ligands and potentiating phosphorylation and signaling through the ErbB2/ErbB3 heterodimeric receptor complex formed in the presence of neuregulin. In contrast, MUC1 has a highly conserved cytoplasmic tail, which binds β‐catenin, a key component of adherens junctions and a regulator of transcription, in a process that is tightly regulated by MUC1 phosphorylation. The specific localization of these membrane mucins to the apical surfaces of epithelial cells suggests that their signaling functions may be important as sensor mechanisms in response to invasion or damage of epithelia. BioEssays 25:66–71, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

The activity of Wnt and Notch signalling is central to many cell fate decisions during development and to the maintenance and differentiation of stem cell populations in homeostasis. While classical views refer to these pathways as independent signal transduction devices that co‐operate in different systems, recent work has revealed intricate connections between their components. These observations suggest that rather than operating as two separate pathways, elements of Wnt and Notch signalling configure an integrated molecular device whose main function (...) is to regulate transitions between cell states in development and homeostasis. Here, we propose a general framework for the structure and function of the interactions between these signalling systems that is focused on the notion of ‘transition states’, i.e. intermediates that arise during cell fate decision processes. These intermediates act as checkpoints in cell fate decision processes and are characterised by the mixed molecular identities of the states involved in these processes.Editor's suggested further reading in BioEssays: Notch: Implications of endogenous inhibitors for therapy Abstract. (shrink)

Vulval development in the Caenorhabditis elegans hermaphrodite represents a simple, genetically tractable system for studying how cell signaling events control cell fata decisions. Current models suggest that proper specification of vulval cell fates relies on the integration of multiple signaling systems, including one that involves a receptor tyrosine kinase (RTK)→Ras→mitogen activated protein kinase (MAPK) cascade and one that involves a LIN‐12/Notch family receptor. In this review, we first discuss how genetic strategies are being used to (...) identify and analyze components that control vulval cell fate decisions. We then describe the different signaling systems that have been elucidated and how they relate to one another. Finally, we highlight several recently characterized genes that encode positive regulators, negative regulators or potential targets of the RTK→Ras→MAPK cascade involved in vulval induction. (shrink)

The endoplasmic reticulum (ER) organelle is the key intracellular site of both protein and lipid biosynthesis. ER dysfunction, termed ER stress, can result in protein accretion within the ER and cell death; a pathophysiological process contributing to a range of metabolic diseases and cancers. ER stress leads to the activation of a protective signalling cascade termed the Unfolded Protein Response (UPR). However, chronic UPR activation can ultimately result in cellular apoptosis. Emerging evidence suggests that cells undergoing ER stress and (...) UPR activation can release extracellular signals that can propagate UPR activation to target tissues in a cell non‐autonomous signalling mechanism. Separately, studies have determined that the UPR plays a key regulatory role in the biosynthesis of bioactive signalling lipids including sphingolipids and ceramides. Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are exported and function as cell non‐autonomous signals to propagate UPR activation in target cells and tissues. (shrink)

Cadherins are a large family of single‐pass transmembrane proteins principally involved in Ca2+‐dependent homotypic cell adhesion. The cadherin molecules comprise three domains, the intracellular domain, the transmembrane domain and the extracellular domain, and form large complexes with a vast array of binding partners (including cadherin molecules of the same type in homophilic interactions and cellular protein catenins), orchestrating biologically essential extracellular and intracellular signalling processes. While current, contrasting models for classic cadherin homophilic interaction involve varying numbers of specific repeats (...) found in the extracellular domain, the structure of the domain itself clearly remains the main determinant of cell stability and binding specificity. Through intracellular interactions, cadherin enhances its adhesive properties binding the cytoskeleton via cytoplasmic associated factors α‐ catenin, β‐catenin and p120ctn. Recent structural studies on classic cadherins and these catenin molecules have provided new insight into the essential mechanisms underlying cadherin‐mediated cell interaction and catenin‐mediated cellular signalling. Remarkable structural diversity has been observed in β‐catenin recognition of other cellular factors including APC, Tcf and ICAT, proteins that contribute to or compete with cadherin/catenin functioning. BioEssays 26:497–511, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The importance of electrical signalling in bacteria is an emerging paradigm. Bacillus subtilis biofilms exhibit electrical communication that regulates metabolic activity and biofilm growth. Starving cells initiate oscillatory extracellular potassium signals that help even the distribution of nutrients within the biofilm and thus help regulate biofilm development. Quorum sensing also regulates biofilm growth and crucially there is convergence between electrical and quorum sensing signalling axes. This makes B. subtilis an interesting model for cell signalling research. SpoOF is predicted to (...) act as a logic gate for signalling pathway convergence, raising interesting questions about the functional nature of this gate and the relative importance of these disparate signals on biofilm behaviour. How is an oscillating signal integrated with a quorum signal? The model presented offers rich opportunities for future experimental and theoretical modelling research. The importance of direct cell‐to‐cell electrical signalling in prokaryotes, so characteristic of multicellular eukaryotes, is also discussed. (shrink)

The vav proto‐oncogene encodes a 95 kDa protein which is expressed exclusively in hematopoietic cells. Analysis of the deduced amino acid sequence has revealed the presence of a src‐homology 2 (SH2) domain, 2 SH3 domains, a cysteine‐rich region with similarity to protein kinase C, and a region highly similar to proteins with guanine nucleotide exchange activity on ras‐like GTPases. Recent work has shown that vav is tyrosine phosphorylated in response to stimulation of surface membrane receptors in a variety of hematopoietic (...) cell lines. Vav may play a role in hematopoietic cell signaling by coupling tyrosine kinase pathways to ras‐like GTPases through the regulation of guanine nucleotide exchange. (shrink)

Hedgehog is an important morphogenic signal that directs pattern formation during embryogenesis, but its activity also remains present through adult life. It is now becoming increasingly clear that during the reproductive phase of life and beyond it continues to direct cell renewal (which is essential to combat the chronic environmental stress to which the body is constantly exposed) and counteracts vascular, osteolytic and sometimes oncological insults to the body. Conversely, down‐regulation of hedgehog signalling is associated with ageing‐related diseases such (...) as type 2 diabetes, neurodegeneration, atherosclerosis and osteoporosis. Hence, in this essay we argue that hedgehog signalling is not only important at the start of life, but also constitutes an important anti‐geriatric influence, and that enhanced understanding of its properties may contribute to developing rational strategies for healthy ageing and prevention of ageing‐related diseases.Also watch the Video Abstract. (shrink)

Timers and sensors are common devices that make our daily life safer, more convenient, and more efficient. In a cellular context, they arguably play an even more crucial role as they ensure the survival of cells in the presence of various extrinsic and intrinsic stresses. Biological timers and sensors generate distinct signaling profiles, enabling them to produce different types of cellular responses. Recent data suggest that they can work together to guarantee correct timing and responsiveness. By exploring examples of (...) cellular stress signaling from mitosis, DNA damage, and hypoxia, the authors discuss the common architecture of timer‐sensor integration, and how its added features contribute to the generation of desired signaling profiles when dealing with stresses of variable duration and strength. The authors propose timer‐sensor integration as a widespread mechanism with profound biological implications and therapeutic potential. -/- . (shrink)

Bone morphogenetic proteins (BMPs) are typically members of the transforming growth factor β (TGF-β) family with diverse roles in embryonic development. At least five genes with homology to BMPs are expressed during Xenopus development, along with their receptors and intracellular signalling pathways. The evidence suggests that BMPs have roles to play in both mesoderm induction and dorsoventral patterning. Studies in Xenopus have also identified a number of inhibitory binding proteins for the classical BMPs, encoded by genes such as chordin and (...) noggin. These proteins appear to be responsible for establishing a morphogen gradient of BMP4 activity, which specifies different dorsoventral fates in early gastrulae. An emerging theme is that inhibition of BMP signalling is an important mechanism regulating cell fate decisions in early development. BioEssays 21:751–760, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Cell proliferation in response to growth factors is mediated by specific high affinity receptors. Ligand‐binding by receptors of the protein tyrosine kinase family results in the stimulation of several intracellular signal transduction pathways. Key signalling enzymes are recruited to the plasma membrane through the formation of stable complexes with activated receptors. These interactions are mediated by the conserved, non‐catalytic SH2 domains present in the signalling molecules, which bind with high affinity and specificity to tyrosine‐phosphorylated sequences on the receptors. The (...) assembly of enzyme complexes is emerging as a major mechanism of signal transduction and may regulate the pleiotropic effects of growth factors. (shrink)

This paper discusses the evidence for the role of CREB in neural stem/progenitor cell (NSPC) function and oncogenesis and how these functions may be important for the development and growth of brain tumours. The cyclic‐AMP response element binding (CREB) protein has many roles in neurons, ranging from neuronal survival to higher order brain functions such as memory and drug addiction behaviours. Recent studies have revealed that CREB also has a role in NSPC survival, differentiation and proliferation. Recent work has (...) shown that over‐expression of CREB in transgenic animals can impart oncogenic properties on cells in various tissues and that aberrant CREB expression is associated with tumours in patients. It is the central position of CREB, downstream of key developmental and growth signalling pathways, which give CREB the ability to influence a spectrum of cell activities, such as cell survival, growth and differentiation in both normal and cancer cells. (shrink)

Neuronal signalling involves multiple neuropeptides that are diverse in structure and function. Complex patterns of tissue‐specific expression arise from alternate RNA splicing of neuropeptide‐encoding gene transcripts. The pattern of expression and its role in cell signalling is diffecult to study at the level of single neurons in the complex vertebrate brain. However, in the model molluscan system, Lymnaea, it is possible to show that alternate mRNA expression of the FMRFamide gene is specific to single identified neurons. Two different transcripts (...) are expressed in a mutually exclusive manner in different neurons. Post‐translational processing of the two precursor proteins leads to completely distinct sets of neuropeptide transmitters. The function of these transmitter cocktails, resulting from alternate mRNA splicing, was studied physiologically in identified neurons forming part of a behaviourally important network regulating heartbeat. (shrink)

Recent findings in several organ systems show that cytoneme‐mediated signaling transports signaling proteins along cellular extensions and targets cell‐to‐cell exchanges to synaptic contacts. This mechanism of paracrine signaling may be a general one that is used by many (or all) cell types in many (or all) organs. We briefly review these findings in this perspective. We also describe the properties of several signaling systems that have previously been interpreted to support a passive diffusion (...) mechanism of signaling protein dispersion, but can now be understood in the context of the cytoneme mechanism.Also watch the Video Abstract. (shrink)

The purinergic signalling system, which utilises ATP, related nucleotides and adenosine as transmitter molecules, appeared very early in evolution: release mechanisms and ATP‐degrading enzymes are operative in bacteria, and the first specific receptors are present in single cell eukaryotic protozoa and algae. Further evolution of the purinergic signalling system resulted in the development of multiple classes of purinoceptors, several pathways for release of nucleotides and adenosine, and a system of ectonucleotidases controlling extracellular levels of purinergic transmitters. The purinergic signalling (...) system is expressed in virtually all types of tissues and cells, where it mediates numerous physiological reactions and contributes to pathological responses in a variety of diseases. (shrink)

Wnt proteins are involved in a large number of events during development and disease. The crucial element in the transduction of the signal elicited by Wnt is the state and activity of β-catenin. There are two pools of β-catenin, one associated with cadherins at the cell surface and a soluble one in the cytolasm, whose state and concentration are critical for Wnt signalling. In the absence of Wnt, the cytoplasmic pool is low due to targetted degradation of β-catenin. Upon (...) Wnt signalling, β-catenin is stabilized. As a consequence, it can access the nucleus where it interacts with members of the Tcf family of transcription factors to modulate the expression of defined targets. Recent reports indicate that, in addition to Tcfs, β-catenin can interact with other nuclear proteins raising the possibility that Wnt signalling has a wider modulatory effect on transcription than is mediated by its interactions with Tcfs. BioEssays 23:311–318, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Adenosine 5′-triphosphate (ATP) was identified in 1970 as the transmitter responsible for non-adrenergic, non-cholinergic neurotransmission in the gut and bladder and the term ‘purinergic’ was coined. Purinergic cotransmission was proposed in 1976 and ATP is now recognized as a cotransmitter in all nerves in the peripheral and central nervous systems. P1 (adenosine) and P2 (ATP) receptors were distinguished in 1978. Cloning of these receptors in the early 1990s was a turning point in the acceptance of the purinergic signalling hypothesis. There (...) are both short-term purinergic signalling in neurotransmission, neuromodulation and secretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation and death in development and regeneration. Much is known about the mechanisms of ATP release and its breakdown by ectonucleotidases. Recently, there has been emphasis on purinergic pathophysiology, including neurodegenerative and neuropsychiatric disorders. Purinergic therapeutic strategies are being developed for treatment of gut, kidney, bladder, lung, skeletal and reproductive system disorders, pain and cancer. (shrink)

Planar cell polarity (PCP) refers to the polarization of a field of cells within the plane of a cell sheet. This form of polarization is required for diverse cellular processes in vertebrates, including convergent extension (CE), the establishment of PCP in epithelial tissues and ciliogenesis. Perhaps the most distinct example of vertebrate PCP is the uniform orientation of stereociliary bundles at the apices of sensory hair cells in the mammalian auditory sensory organ. The establishment of PCP in the (...) mammalian cochlea occurs concurrently with CE in this ciliated epithelium, therefore linking three cellular processes regulated by the vertebrate PCP pathway in the same tissue and emerging as a model system for dissecting PCP signaling. This review summarizes the morphogenesis of this model system to assist the interpretation of the emerging data and proposes molecular mechanisms underlying PCP signaling in vertebrates. BioEssays 29: 120–132, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Notch is a mechanosensitive receptor that requires direct cell–cell contact for its activation. Both the strength and the range of notch signaling depend on the size and geometry of the contact sites between cells. These properties of cell–cell contacts in turn depend on cell shape and polarity. At the molecular level, the E3 ubiquitin ligase Neuralized links receptor activation with epithelial cell remodeling. Neur regulates the endocytosis of the Notch ligand Delta, hence Notch (...) activation. It also targets the apical polarity protein Stardust to promote the endocytosis of the Crumbs complex, thereby contributing to epithelium remodeling. Here, we review the interplay between Notch signaling and cell polarity and discuss the possible significance of linking Notch signaling with epithelial cell polarity via a common regulator. Notch receptor activation depends on direct cell–cell contacts that in turn depends on cell shape and cellular polarity. The size and geometry of cell–cell contacts have an impact on the strength and range of signaling. The E3 ubiquitin ligase Neuralized regulates the endocytosis and signaling activity of Delta. The activity of Neuralized is tightly regulated during development. Neuralized also modulates epithelial cell polarity by targeting the apical polarity protein Stardust and by promoting the endocytosis of Crumbs. Thus, the cell-specific expression of Neuralized couples Notch receptor activation with cell polarity regulation in epithelia. (shrink)

Notch is a mechanosensitive receptor that requires direct cell–cell contact for its activation. Both the strength and the range of notch signaling depend on the size and geometry of the contact sites between cells. These properties of cell–cell contacts in turn depend on cell shape and polarity. At the molecular level, the E3 ubiquitin ligase Neuralized links receptor activation with epithelial cell remodeling. Neur regulates the endocytosis of the Notch ligand Delta, hence Notch (...) activation. It also targets the apical polarity protein Stardust to promote the endocytosis of the Crumbs complex, thereby contributing to epithelium remodeling. Here, we review the interplay between Notch signaling and cell polarity and discuss the possible significance of linking Notch signaling with epithelial cell polarity via a common regulator. Notch receptor activation depends on direct cell–cell contacts that in turn depends on cell shape and cellular polarity. The size and geometry of cell–cell contacts have an impact on the strength and range of signaling. The E3 ubiquitin ligase Neuralized regulates the endocytosis and signaling activity of Delta. The activity of Neuralized is tightly regulated during development. Neuralized also modulates epithelial cell polarity by targeting the apical polarity protein Stardust and by promoting the endocytosis of Crumbs. Thus, the cell-specific expression of Neuralized couples Notch receptor activation with cell polarity regulation in epithelia. (shrink)

It has long been thought that transmembrane cell‐surface receptors, such as receptor tyrosine kinases and cytokine receptors, among others, are activated by ligand binding through ligand‐induced dimerization of the receptors. However, there is growing evidence that prior to ligand binding, various transmembrane receptors have a preformed, yet inactive, dimeric structure on the cell surface. Various studies also demonstrate that during transmembrane signaling, ligand binding to the extracellular domain of receptor dimers induces a rotation of transmembrane domains, followed (...) by rearrangement and/or activation of intracellular domains. The paper here describes transmembrane cell‐surface receptors that are known or proposed to exist in dimeric form prior to ligand binding, and discusses how these preformed dimers are activated by ligand binding. (shrink)

Steroid hormones are signaling molecules important for normal growth, development and differentiation of multicellular organisms. Brassinosteroids (BRs) are a class of polyhydroxylated steroids that are necessary for plant development. Molecular genetic studies in Arabidopsis thaliana have led to the cloning and characterization of the BR receptor, BRI1, which is a transmembrane receptor serine/threonine kinase. The extracellular domain of BRI1, which is composed mainly of leucine‐rich repeats, can confer BR responsivity to heterologous cells and is required for BR binding. Although (...) downstream components of BR action are mostly unknown, multiple genes whose expression are regulated by BRs have been identified and suggest mechanisms by which BRs affect cell elongation and division. BioEssays 23:1028–1036, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Precision cell signaling activities of reactive electrophilic species (RES) are arguably among the most poorly‐understood means to transmit biological messages. Latest research implicates native RES to be a chemically‐distinct subset of endogenous redox signals that influence cell decision making through non‐enzyme‐assisted modifications of specific proteins. Yet, fundamental questions remain regarding the role of RES as bona fide second messengers. Here, we lay out three sets of criteria we feel need to be met for RES to be considered (...) as true cellular signals that directly mediate information transfer by modifying “first‐responding” sensor proteins. We critically assess the available evidence and define the extent to which each criterion has been fulfilled. Finally, we offer some ideas on the future trajectories of the electrophile signaling field taking inspiration from work that has been done to understand canonical signaling mediators. (shrink)

The cellular capacity to internalise objects, involving attachment, engulfment and uptake, exists in virtually all organisms. Many uptake reactions are associated with cell signalling. However, the mechanical forces that form endocytotic vesicles are not known. We propose a ‘leverage‐mediated’ uptake mechanism involving lateral cross‐linking processes on the cell surface that can generate the configurational energy to create an inverse curvature of the membrane. BioEssays 26:1344–1350, 2004. © 2004 Wiley Periodicals, Inc.

The mitogenic action of cytokines such as epidermal growth factor (EGF)d̊ or platelet dericed growth factor (PDGF) involves the stimulation of a signal cascade controlled by a small G protein called Ras. Mutations of Ras can cause its constitutive activation and, as a consequence, bypass the regulation of cell growth by cytokines. Both growth factor‐induced and oncogenic activation of Ras involve the conversion of Ras from the GDP‐bound (D‐Ras) to the GTP‐bound (T‐Ras) forms. T‐Ras activates a network of protein (...) kinases including c‐Mos, c‐Raf‐1 and MAP kinase. Eventually the activation of MAP kinase leads to the activation of the elongation factor 4E and several transcription factors such as c‐Jun, c‐Myc and c‐Fos. There are several modulators of Ras activity, such as the GTPase activating proteins (GAP1 and NF1), which stimulate the coversion of T‐Ras to D‐Ras. A series of small NF1 fragments, which bind T‐Ras, as well as truncated forms or derivatives of c‐Raf‐1, c‐Jun and c‐Myc, are capable of blocking the T‐Ras‐activated mitogenesis in a competitive manner. These agents offer a unique opportunity to control the proliferation of T‐Ras‐associated tumors, which represent more than 30% of total human carcinomas. (shrink)

Pancreatic β‐cells in the islet of Langerhans produce the hormone insulin, which maintains blood glucose homeostasis. Perturbations in β‐cell function may lead to impairment of insulin production and secretion and the onset of diabetes mellitus. Several essential β‐cell factors have been identified that are required for normal β‐cell function, including six genes that when mutated give rise to inherited forms of diabetes known as Maturity Onset Diabetes of the Young (MODY). However, the intracellular signaling pathways that (...) control expression of MODY and other factors continue to be revealed. Post‐transplant diabetes mellitus in patients taking the calcineurin inhibitors tacrolimus (FK506) or cyclosporin A indicates that calcineurin and its substrate the Nuclear Factor of Activated T‐cells (NFAT) may be required for β‐cell function. Here recent advances in our understanding of calcineurin and NFAT signaling in the β‐cell are reviewed. Novel therapeutic approaches for the treatment of diabetes are also discussed. BioEssays 29:1011–1021, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The formation of blood vessels within the vascular system entails a variety of cellular processes, including proliferation, migration and differentiation. In many cases, these diverse processes need to be finely coordinated among neighbouring endothelial cells in order to establish a functional vascular network. For instance, during angiogenic sprouting specialized endothelial tip cells follow guidance cues and migrate extensively into avascular tissues while trailing stalk cells must stay connected to the patent blood vessel. The vascular endothelial growth factor (VEGF) and Notch (...) signalling pathways have emerged as the major players in governing these different cellular behaviours. In particular, recent work indicates an important role for Notch signalling in determining how an endothelial cell responds to VEGF. In this review, we provide an overview of these biochemically distinct pathways and discuss how they may interact during endothelial cell differentiation and angiogenesis. BioEssays 30:303–313, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The discovery of the first intracellular substrate for insulin, IRS‐1, redirected the field of diabetes research and has led to many important advances in our understanding of insulin action. Detailed analysis of IRS‐1 demonstrates structure/function relationships for this modular docking molecule, including mechanisms of substrate recognition and signal propagation. Recent work has also identified other structurally similar molecules, including IRS‐2, the Drosophila protein, DOS, and the Grb2‐binding protein, Gab1, suggesting that this intracellular signalling strategy is conserved evolutionarily and is utilized (...) by an expanding number of receptor systems. In fact, IRS‐1 itself has been shown to be important in other growth factor and cytokine signalling systems, including growth hormone and several interleukins. Analysis of mice lacking IRS‐1 confirms an important physiological role for this protein in glucose metabolism and general cell growth in the intact animal. Disregulation of the signalling pathways integrated by the IRS proteins may contribute to the pathophysiology of non‐insulin‐dependent diabetes mellitus or other diseases. (shrink)

Receptor tyrosine kinases and integrins are activated by growth factors and extracellular matrix, respectively. Their activation leads to signal transduction cascades that control many aspects of cell phenotype, including progression through the G1 phase of the cell cycle. However, the signalling cassettes driven by growth factors and matrix do not work independently of each other. Integrin triggering is essential to facilitate kinase‐ and GTPase‐mediated signals and thereby drive efficient transfer of information through the growth factor–cyclin axis. A recent (...) study indicates that an additional type of player has a key role in adhesion‐regulated control of cell cycle, namely ubiquitin ligase.(1) BioEssays 24:17–21, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

The common neurotrophin receptor (p75NTR) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by p75NTR‐mediated signals following activation by either mature or pro‐neurotrophins and in combination with various co‐receptors, including Trk receptors and sortilin. Here, we review the known functions of p75NTR by cell type, receptor‐ligand combination, and whether regulated intra‐membrane proteolysis of p75NTR is required for (...) signalling. We highlight that the generation of the intracellular domain fragment of p75NTR is associated with many of the receptor functions, regardless of its ligand and co‐receptor interactions. (shrink)

Integrin‐mediated cell adhesion and subsequent cell spreading are essential for the growth and survival of many cell types. While integrin engagement is known to activate various signalling pathways, the role that cell spreading plays in the control of growth and survival is not clear. Using a novel technique, however, Chen et al.(1) demonstrate that the effect of cell spreading on growth and survival is not a consequence of increased area of contact with the extracellular matrix, (...) supporting the hypothesis that regulation through changes in cell tension and architecture play a key role. (shrink)

Determination of cell fate in the developing eye of Drosophila depends on a precise sequence of cellular interactions which generate the stereotypic array of ommatidia. In the eye imaginal disc, an initially unpatterned epithelial sheath of cells, the first step in this process may be the specification of R8 photoreceptor cells at regular intervals. Genes such as Notch and scabrous, known to be involved in bristle development, alos participate in this process, suggesting that the specification of ommatidial founder cells (...) and the formation of sensory organs in the adult epidermis may involve a similar mechanism, that of lateral inhibition. The subsequent steps of ommatidial assembly, following R8 assignment, involve a different mechanism: Undetermined cells read their position based on the contacts they make with neighbors that have already begun to differentiate. The development of the R7 photoreceptor cell, one of the eight photoreceptor cells in the ommatidium, is best understood. An important role seems to be played by sevenless, a receptor tyrosine kinase on the surface of the R7 precursor. It transmits the positional information– most likely encoded by the boss protein on the neighboring R8 cell membrane – into the cell via its tyrosine kinase, which activates a signal transduction cascade. Constitutive activation of the sevenless kinase by overexpression of an N‐terminally truncated form results in the diversion of other ommatidial cells into the R7 pathway suggesting that activation of the sevenless signalling pathway is sufficient to specify R7 development. Genetic dissection of this pathway should therefore identify components of a signalling cascade activated by a tyrosine kinase. (shrink)

How epithelial tissues are able to self-renew to maintain homeostasis and regenerate in response to injury remains a persistent question. The transcriptional effectors YAP and TAZ are increasingly being recognized as central mediators of epithelial stem cell biology, and a wealth of recent studies have been directed at understanding the control and activity of these factors. Recent work by Hu et al. has added to this knowledge, as they identify an Integrin-FAK-CDC42-PP1A signaling cascade that directs nuclear YAP/TAZ activity (...) in stem cell populations of the mouse incisor, and define convergence on mTORC1 signaling as an important mediator of the proliferation of these cells. Here, we review recent studies on YAP/TAZ function and regulation in epithelial tissue-specific stem cells, merging the Hu et al. study together with our current knowledge of YAP/TAZ. The Hippo pathway effectors YAP and TAZ broadly regulate adult stem cells, and have recently been implicated in dental epithelial stem cell proliferation and restricted differentiation via an Integrin-FAK-CDC42-PP1A cascade. Here, we discuss the extracellular cues which control YAP/TAZ activity and examine downstream pathways that direct stem cell fate. (shrink)

How epithelial tissues are able to self-renew to maintain homeostasis and regenerate in response to injury remains a persistent question. The transcriptional effectors YAP and TAZ are increasingly being recognized as central mediators of epithelial stem cell biology, and a wealth of recent studies have been directed at understanding the control and activity of these factors. Recent work by Hu et al. has added to this knowledge, as they identify an Integrin-FAK-CDC42-PP1A signaling cascade that directs nuclear YAP/TAZ activity (...) in stem cell populations of the mouse incisor, and define convergence on mTORC1 signaling as an important mediator of the proliferation of these cells. Here, we review recent studies on YAP/TAZ function and regulation in epithelial tissue-specific stem cells, merging the Hu et al. study together with our current knowledge of YAP/TAZ. The Hippo pathway effectors YAP and TAZ broadly regulate adult stem cells, and have recently been implicated in dental epithelial stem cell proliferation and restricted differentiation via an Integrin-FAK-CDC42-PP1A cascade. Here, we discuss the extracellular cues which control YAP/TAZ activity and examine downstream pathways that direct stem cell fate. (shrink)

Integrins are ubiquitous trans‐membrane adhesion molecules that mediate the interaction of cells with the extracellular matrix (ECM). Integrins link cells to the ECM by interacting with the cell cytoskeleton. In cases such as leukocyte binding, integrins mediate cell‐cell interactions and cell‐ECM interactions. Recent research indicates that integrins also function as signal transduction receptors, triggering a number of intracellular signaling pathways that regulate cell behavior and development. A number of integrins are known to stimulate changes (...) in intracellular calcium levels, resulting in integrin activation. Although changes in intracellular calcium regulate a vast number of cellular functions, this review will discuss the stimulation of calcium signaling by integrins and the role of intracellular calcium in the regulation of integrin‐mediated adhesion. (shrink)

The YAP/TAZ family of transcriptional co‐activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB‐Hippo/MST‐Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal (...) signalling occurs via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST‐LATS or Src family kinase activity to modulate YAP/TAZ activity. (shrink)

The common neurotrophin receptor (p75NTR) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by p75NTR‐mediated signals following activation by either mature or pro‐neurotrophins and in combination with various co‐receptors, including Trk receptors and sortilin. Here, we review the known functions of p75NTR by cell type, receptor‐ligand combination, and whether regulated intra‐membrane proteolysis of p75NTR is required for (...) signalling. We highlight that the generation of the intracellular domain fragment of p75NTR is associated with many of the receptor functions, regardless of its ligand and co‐receptor interactions. (shrink)

Abstractβ‐Catenin/CTNNB1 is critical for leukemia initiation or the stem cell capacity of several hematological malignancies. This review focuses on a general evaluation of β‐catenin function in normal T‐cell development and T‐cell acute lymphoblastic leukemia (T‐ALL). The integration of the existing literature offers a state‐of‐the‐art dissection of the complexity of β‐catenin function in leukemia initiation and maintenance in both Notch‐dependent and independent contexts. In addition, β‐catenin mutations are screened for in T‐ALL primary samples, and it is found that (...) they are rare and with little clinical relevance. Transcriptional analysis of Wnt family members (Ctnnb1, Axin2, Tcf7, and Lef1) and Myc in different publicly available T‐ALL cohorts indicates that the expression of these genes may correlate with T‐ALL subtypes and/or therapy outcomes. (shrink)

During the formation of the brain, neuronal cell migration and neurite extension are controlled by extracellular guidance cues. Here, I discuss experiments showing that the messenger nitric oxide (NO) is an additional regulator of cell motility. NO is a membrane permeant molecule, which activates soluble guanylyl cyclase (sGC) and leads to the formation of cyclic GMP (cGMP) in target cells. The analysis of specific cells types in invertebrate models such as molluscs, insects and the medicinal leech provides insight (...) how NO and cyclic nucleotides affect the wiring of nervous systems by regulating cell and growth‐cone motility. Inhibition of the NOS and sGC enzymes combined with rescue experiments show that NO signalling orchestrates neurite outgrowth and filopodial dynamics, cell migration of enteric neurons, glial migration and axonogenesis of pioneer fibers. Cultured insect embryos are accessible model systems in which cellular mechanisms of NO‐induced cytoskeletal reorganizations can be analyzed in natural settings. Finally, I will outline some indications that NO may also regulate cell motility in the developing and regenerating vertebrate nervous system. BioEssays 27:495–505, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Competence is an active state that defines the way in which cells respond to an inductive signal. A challenge of developmental biology is to explain not just the nature of the signalling molecules that promote cell specification or differentiation, but also how cells acquire competence to respond to these signals and what that reflects in molecular terms. A recent paper by Carmena et al.(1) has revealed how several signalling mechanisms are used sequentially and in specific combinations to specify two (...) mesodermal lineages in Drosophila. BioEssays 21:455–458, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Muscular dystrophies are associated with mutations in genes encoding several classes of proteins. These range from extracellular matrix and integral membrane proteins to cytoskeletal proteins, but also include a heterogeneous group of proteins including proteases, nuclear proteins, and signalling molecules. Muscular dystrophy phenotypes have also become evident in studies on various knockout mice defective in proteins not previously considered or known to be mutated in muscular dystrophies. Some unifying themes are beginning to emerge from all of these data. This review (...) will consider recent advances in our understanding of the molecules involved and bring together data that suggest a role for the cytoskeleton and cell adhesion in muscular dystrophies. BioEssays 24:542–552, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Retinoids play a critical role in patterning, segmentation, and neurogenesis of the posterior hindbrain and it has been proposed that they act as a posteriorising signal during hindbrain development. Until now, direct evidence that endogenous retinoid signalling acts through a gradient to specify cell fates along the anteroposterior axis has been missing. Two recent studies tested the requirement for retinoid signalling in the developing hindbrain through systematic application of a pan-retinoic acid receptor antagonist.(1,2) They demonstrate a stage-dependent requirement for (...) increasing retinoid signalling activity along the hindbrain that proceeds from anterior to posterior. Together these findings challenge the concept of a stable gradient of retinoic acid across the hindbrain and warrant a re-interpretation of the phenotypes obtained by genetic and nutritional disruption of retinoid signalling in the amniote embryo. BioEssays 23:981–986, 2001. © 2001 John Wiley & Sons, Inc. (shrink)