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)

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 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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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 tricarboxylic acid (TCA) or Krebs cycle, which takes place in prokaryotic cells and in the mitochondria of eukaryotic cells, is central to life on Earth and participates in key events such as energy production and anabolic processes. Despite its relevance, it is not perceived as tightly regulated compared to other key metabolisms such as glycolysis/gluconeogenesis. A better understanding of the functioning of the TCA cycle is crucial due to mitochondrial function impairment in several diseases, especially those that occur with (...) neurodegeneration. This article revisits what is known about the regulation of the Krebs cycle and hypothesizes the need for large‐scale, rapid regulation of TCA cycle enzyme activity. Evidence of mitochondrial enzyme activity regulation by activation/deactivation of protein kinases and phosphatases exists in the literature. Apart from indirect regulation via G protein‐coupled receptors (GPCRs) at the cell surface, signaling upon activation of GPCRs in mitochondrial membranes may lead to a direct regulation of the enzymes of the Krebs cycle. Hormonal‐like regulation by posttranscriptional events mediated by activable kinases and phosphatases deserve proper assessment using isolated mitochondria. Also see the video abstract here: https://youtu.be/aBpDSWiMQyI. (shrink)

The Liver kinase B1 with its downstream target AMP activated protein kinase (LKB1‐AMPK), and the key nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) form two signaling systems that coordinate metabolic and cellular activity with changes in the environment in order to preserve homeostasis. For example, nutritional fluctuations rapidly feed back on these signaling systems and thereby affect cell‐specific functions. Recent studies have started to reveal important roles of these strategic metabolic regulators in Schwann cells for (...) the trophic support and myelination of axons. Because aberrant intermediate metabolism along with mitochondrial dysfunction in Schwann cells is mechanistically linked to nerve abnormalities found in acquired and inherited peripheral neuropathies, manipulation of the LKB1‐AMPK, and mTORC1 signaling hubs may be a worthwhile therapeutic target to mitigate nerve damage in disease. Here, recent advances in our understanding of LKB1‐AMPK and mTORC1 functions in Schwann cells are covered, and future research areas for this key metabolic signaling network are proposed. (shrink)

Recent work by Fernández‐Sánchez and coworkers examining the impact of applied pressure on the malignant phenotype of murine colon tissue in vivo revealed that mechanical perturbations can drive malignant behavior in genetically normal cells. Their findings build upon an existing understanding of how the mechanical cues experienced by cells within a tissue become progressively modified as the tissue transforms. Using magnetically stimulated ultra‐magnetic liposomes to mimic tumor growth ‐induced solid stress, Fernández‐Sánchez and coworkers were able to stimulate β‐catenin to promote (...) the cancerous behavior of both a normal and genetically modified colon epithelium. In this perspective, we discuss their findings in the context of what is currently known regarding the role of the mechanical landscape in cancer progression and β‐catenin as a mechanotransducer. We review data that suggest that mechanically regulated activation of β‐catenin fosters development of a malignant phenotype in tissue and predict that mechanical cues may contribute to tumor heterogeneity. (shrink)

What are the functional units of the brain? If the function of the brain is to process information-carrying signals, then the functional units will be the senders and receivers of those signals. Neurons have been the default candidate, with action potentials as the signals. But there are alternatives: synapses fit the action potential picture more cleanly, and glial activities (e.g., in astrocytes) might also be characterized as signaling. Are synapses or nonneuronal cells better candidates to play the role of (...) functional units? Will informational signaling still be the best model for brain function if we move beyond the neuron doctrine? (shrink)

Intercellular signaling plays a major role in the development of vertebrate and invertebrate embryos. In several cases, including the induction of mesoderm and neural ectoderm induction in Xenopus and the induction of the vulva in C. elegans, multiple intercellular signals are utilized. This review examines a number of examples of signaling in development wherein two signals combine to affect the fate of a cell. The examples are placed in distinct categories, based on whether the signals synergize with (...) or antagonize one another, and on the inductive potential of the individual signals. These types of combinatorial signaling events are suggested to be a general feature of embryonic development. (shrink)

The evolutionarily conserved Notch signaling pathway regulates a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal life. It is involved in embryonic organogenesis as well as in the maintenance of homeostasis of self‐renewing systems. In this article, we review the role of Notch signaling in the hematopoietic system with particular emphasis on lymphocyte development and highlight the similarities in Notch function between Drosophila and mammalian differentiation processes. Recent studies indicating that aberrant NOTCH (...) signaling is frequently linked to the induction of T leukemia in humans will also be discussed. BioEssays 27:1117–1128, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Platelets have important hemostatic functions in repairing blood vessels upon tissue injury. Cytokines, growth factors, and metabolites stored in platelet α‐granules and dense granules are released upon platelet activation and clotting. Emerging evidence indicates that such platelet‐derived signaling factors are instrumental in guiding tissue regeneration. Here, we discuss the important roles of platelet‐secreted signaling factors in skeletal muscle regeneration. Chemokines secreted by platelets in the early phase after injury are needed to recruit neutrophils to injured muscles, and impeding (...) this early step of muscle regeneration exacerbates inflammation at later stages, compromises neo‐angiogenesis and the growth of newly formed myofibers, and reduces post‐injury muscle force production. Platelets also contribute to the recruitment of pro‐regenerative stromal cells from the adipose tissue, and the platelet releasate may also regulate the metabolism and proliferation of muscle satellite cells, which sustain myogenesis. Therefore, harnessing the signaling functions of platelets and the platelet secretome may provide new avenues for promoting skeletal muscle regeneration in health and disease. (shrink)

Germ cells are cross-roads of development and evolution. They define the origin of every new generation and, at the same time, represent the biological end-product of any mature organism. Germ cells are endowed with the following capacities: to store a self-descriptive program, to accumulate a protein-synthesizing machinery, and to incorporate enough nourishment to sustain embryonic development. To accomplish this goal, germ cells do not simply unfold a pre-determined program or realize a sole instructive role. On the contrary, due to the (...) complexity of their cytoarchitecture and the nature of the soma-to-germ interactions, they are heavily involved in processes of sign recognition and meaningful tissue exploration. At each stage of their inward migration, germ plasma membranes act as semiotic interfaces allowing cells to interact with the surrounding extracellular milieu and experience the compatibility of selected developmental sequences. The question of which signaling pathways are activated at each developmental stage does not result from a strictly predetermined program instructing germ cell stemness. Rather, each developmental sequence is an open-ended semiotic relationship explored and gradually defined during evolution by the context-dependency of specific cell-to-cell interactions. In this way, any structural and functional novelty that has emerged in the course of germ cell interactions may be interpreted as an exaptation fixed in the species genome in response to specific environmental constraints. (shrink)

Imagine cells that live in a high‐gradient magnetic field (HGMF). Through what mechanisms do the cells sense a non‐uniform magnetic field and how such a field changes the cell fate? We show that magnetic forces generated by HGMFs can be comparable to intracellular forces and therefore may be capable of altering the functionality of an individual cell and tissues in unprecedented ways. We identify the cellular effectors of such fields and propose novel routes in cell biology predicting (...) new biological effects such as magnetic control of cell‐to‐cell communication and vesicle transport, magnetic control of intracellular ROS levels, magnetically induced differentiation of stem cells, magnetically assisted cell division, or prevention of cells from dividing. On the basis of experimental facts and theoretical modeling we reveal timescales of cellular responses to high‐gradient magnetic fields and suggest an explicit dependence of the cell response time on the magnitude of the magnetic field gradient. (shrink)

Focal adhesion kinase (FAK) is a nonreceptor protein‐tyrosine kinase implicated in controlling cellular responses to the engagement of cell‐surface integrins, including cell spreading and migration, survival and proliferation. Aberrant FAK signaling may contribute to the process of cell transformation by certain oncoproteins, including v‐Src. Progress toward elucidating the events leading to FAK activation following integrin‐mediated cell adhesion, as well as events downstream of FAK, has come through the identification of FAK phosphorylation sites and interacting proteins. (...) A signaling partnership is formed between FAK and Src‐family kinases, leading to tyrosine phosphorylation of FAK and associated ‘docking’ proteins Cas and paxillin. Subsequent recruitment of proteins containing Src homology 2 domains, including Grb2 and c‐Crk, to the complex is likely to trigger adhesion‐induced cellular responses, including changes to the actin cytoskeleton and activation of the Ras‐MAP kinase pathway. (shrink)

In this article we discuss the molecular signaling mechanisms that coordinate interactions between Schwann cells and the neurons of the peripheral nervous system. Such interactions take place perpetually during development and in adulthood, and are critical for the homeostasis of the peripheral nervous system (PNS). Neurons provide essential signals to control Schwann cell functions, whereas Schwann cells promote neuronal survival and allow efficient transduction of action potentials. Deregulation of neuron–Schwann cell interactions often results in developmental abnormalities and (...) diseases. Recent investigations have shown that during development, neuronally provided signals, such as Neuregulin, Jagged, and Wnt interact to fine‐tune the Schwann cell lineage progression. In adult, the signal exchange between neurons and Schwann cells ensures proper nerve function and regeneration. Identification of the mechanisms of neuron–Schwann cell interactions is therefore essential for our understanding of the development, function and pathology of the peripheral nervous system as a whole. -/- . (shrink)

We propose a signaling pathway in which cell‐extracellular matrix (ECM) adhesion components PINCH‐1 and kindlin‐2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH‐1 expression via integrin signaling, which suppresses dynamin‐related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin‐2 translocation into mitochondria and interaction with Δ1‐pyrroline‐5‐carboxylate (P5C) reductase 1 (PYCR1). Kindlin‐2 interaction with PYCR1 protects the latter (...) from proteolytic degradation, leading to elevated PYCR1 level. Additionally, PINCH‐1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression. (shrink)

The ATM protein kinase is centrally involved in the cellular response to ionizing radiation (IR) and other DNA double‐strand‐break‐inducing insults. Although it has been well established that IR exposure activates the ATM kinase domain, the actual mechanism by which ATM responds to damaged DNA has remained enigmatic. Now, a landmark paper provides strong evidence that DNA‐strand breaks trigger widespread activation of ATM through changes in chromatin structure.1 This review discusses a checkpoint activation model in which chromatin perturbations lead to the (...) conversion of inactive ATM domains to phosphorylated, active ATM monomers. The new findings underscore the critical importance of epigenetic events in genome function and surveillance in mammalian cells. BioEssays 25:627–630, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Ever since it was discovered in hydra, regeneration has remained a stimulating question for developmental biologists. Cellular approaches have revealed that, within the first few hours of apical or basal hydra regeneration, differentiation and determination of nerve cells are the primary cellular events detectable. The head and foot activators (HA, FA), neuropeptides that are released upon injury, are signaling molecules involved in these processes. In conditions where it induces cellular differentiation or determination, HA behaves as an agonist of the (...) cyclic AMP (cAMP) pathway involving the modulation of CREB nuclear transcription factor activity. This cascade would be required for proper regeneration, regardless of whether the polarity involved is apical or basal. Modulations of the protein kinase C pathway, which have been shown to affect apical or basal positional values, might signal to bring about this polarity; however, endogenous ligands responsible for this modulation are as yet unknown. (shrink)

Before a cell divides into two daughter cells, it typically doubles not only its DNA, but also its mass. Numerous studies in cells ranging from yeast to mammals have shown that cellular growth, stimulated by nutrients and/or growth factor signaling, is a prerequisite for cell cycle progression in most types of cells. The textbook view of growth‐regulated cell cycles is that growth signaling activates the transcription of G1 Cyclin genes to induce cell proliferation, and (...) also stimulates anabolic metabolism and cell growth in parallel. However, genetic knockout tests in model organisms indicate that this is not the whole story, and new studies show that additional, “smarter” mechanisms help to coordinate the cell cycle with growth itself. Here we summarize recent advances in this field, and discuss current models in which growth signaling regulates cell proliferation by targeting core cell cycle regulators via non‐transcriptional mechanisms. (shrink)

Through statistical analysis of datasets describing single cell shape following systematic gene depletion, we have found that the morphological landscapes explored by cells are composed of a small number of attractor states. We propose that the topology of these landscapes is in large part determined by cell‐intrinsic factors, such as biophysical constraints on cytoskeletal organization, and reflects different stable signaling and/or transcriptional states. Cell‐extrinsic factors act to determine how cells explore these landscapes, and the topology of (...) the landscapes themselves. Informational stimuli primarily drive transitions between stable states by engaging signaling networks, while mechanical stimuli tune, or even radically alter, the topology of these landscapes. As environments fluctuate, the topology of morphological landscapes explored by cells dynamically adapts to these fluctuations. Finally we hypothesize how complex cellular and tissue morphologies can be generated from a limited number of simple cell shapes. (shrink)

Phagocytosis is an uptake of large particles governed by the actin-based cytoskeleton. Binding of particles to specific cell surface receptors is the first step of phagocytosis. In higher Eucaryota, the receptors able to mediate phagocytosis are expressed almost exclusively in macrophages, neutrophils, and monocytes, conferring immunodefence properties to these cells. Receptor clustering is thought to occur upon particle binding, that in turn generates a phagocytic signal. Several pathways of phagocytic signal transduction have been identified, including the activation of tyrosine (...) kinases and (or) serine/threonine kinase C in pivotal roles. Kinase activation leads to phosphorylation of the receptors and other proteins, recruited at the sites of phagocytosis. Monomeric GTPases of the Rho and ARF families are likely to be engaged downstream of activated receptors. The GTPases, in cooperation with phosphatidylinositol 4-phosphate 5-kinase and phosphatidylinositol 3-kinase lipid modifying enzymes, can modulate locally the assembly of the submembranous actin filament system leading to particle internalization. BioEssays 21:422–431, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Cell membranes experience frequent stretching and poking: from cytoskeletal elements, from osmotic imbalances, from fusion and budding of vesicles, and from forces from the outside. Are the ensuing changes in membrane tension localized near the site of perturbation, or do these changes propagate rapidly through the membrane to distant parts of the cell, perhaps as a mechanical mechanism of long‐range signaling? Literature statements on the timescale for membrane tension to equilibrate across a cell vary by a (...) factor of ≈106. This study reviews and discusses how apparently contradictory findings on tension propagation in cells can be evaluated in the context of 2D hydrodynamics and poroelasticity. Localization of tension in the cell membrane is likely critical in governing how membrane forces gate ion channels, set the subcellular distribution of vesicle fusion, and regulate the dynamics of cytoskeletal growth. Furthermore, in this study, it is proposed that cells can actively regulate the degree to which membrane tension propagates by modulating the density and arrangement of immobile transmembrane proteins. Also see the video abstract here https://youtu.be/T6K7AIAqqBs. (shrink)

Design patterns are generalized solutions to frequently recurring problems. They were initially developed by architects and computer scientists to create a higher level of abstraction for their designs. Here, we extend these concepts to cell biology to lend a new perspective on the evolved designs of cells' underlying reaction networks. We present a catalog of 21 design patterns divided into three categories: creational patterns describe processes that build the cell, structural patterns describe the layouts of reaction networks, and (...) behavioral patterns describe reaction network function. Applying this pattern language to the E. coli central metabolic reaction network, the yeast pheromone response signaling network, and other examples lends new insights into these systems. (shrink)

The Drosophila compound eye is an excellent experimental system for analysing fate induction of identifiable single cells. Each ommatidium, a unit eye, contains eight photoreceptors (R1‐R8), and the differentiation of these photoreceptors occurs in the larval eye imaginal disc in discrete steps: first R8 is determined, then R2/R5, R3/R4, R1/R6 and finally R7. Induction of R7, in particular, has been extensively studied at the molecular level. The R8 photoreceptor presents on its surface a ligand, Bride of Sevenless, that binds and (...) activates Sevenless receptor tyrosine kinase in the R7 precursor. Autophosphorylated Sevenless initiates a Ras1‐mediated cascade, which eventually activates transcription factors in the nucleus via Raf1 and MAP kinases, resulting in R7 development. However, recent studies indicate that Sevenless (Sev) functions just to neuralize the cell and has no role in R7 fate determination per se. It appears that the R7 fate may represent the lowest rung of a ‘neuronal ground state’, which is attained without any specific inductive cue. It is plausible that the R7 precursor is actively prevented from taking on the neuronal fate and this inhibition is removed by activation of Sev. (shrink)

Phosphatidylinositol‐3‐kinases (PI3Ks) are lipid kinases that produce 3‐phosphorylated derivatives of phosphatidylinositol upon activation by various cues. These 3‐phosphorylated lipids bind to various protein effectors to control many cellular functions. Lipid phosphatases such as phosphatase and tensin homolog (PTEN) terminate PI3K‐derived signals and are critical to ensure appropriate signaling outcomes. Many lines of evidence indicate that PI3Ks and PTEN, as well as some specific lipid effectors are highly compartmentalized, either in plasma membrane nanodomains or in endosomal compartments. We examine the (...) evidence for specific recruitment of PI3Ks, PTEN, and other related enzymes to membrane nanodomains and endocytic compartments. We then examine the hypothesis that scaffolding of the sources (PI3Ks), terminators (PTEN), and effectors of these lipid signals with a common plasma membrane nanodomain may achieve highly localized lipid signaling and ensure selective activation of specific effectors. This highlights the importance of spatial regulation of PI3K signaling in various physiological and disease contexts. (shrink)

Intercellular signaling by growth factors, hormones and neurotransmitters produces second messenger molecules such as cyclic adenosine monophosphate (cAMP) and diacylglycerol (DAG). Protein Kinase A and Protein Kinase C are the principal effector proteins of these prototypical second messengers in certain cell types. Recently, novel receptors for cAMP and DAG have been identified. These proteins, designated EPAC (Exchange Protein directly Activated by cAMP) or cAMP‐GEF (cAMP regulated Guanine nucleotide Exchange Factor) and CalDAG‐GEF (Calcium and Diacylglycerol regulated Guanine nucleotide Exchange (...) Factor) or RasGRP (Ras Guanine nucleotide Releasing Protein) are able to mediate some of the physiologic effects of the second messengers in a protein‐kinase‐independent fashion. These proteins are exchange factors for Ras family GTPases that operate in pathways that run parallel to the classic kinase‐dependent pathways. The rapidly emerging recognition of the functions of these “non‐kinase” effectors in diverse processes such as insulin secretion, thymocyte development, asthma and malignant transformation creates new opportunities for discovery and identifies potential new therapeutic targets. BioEssays 26:730–738, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

When cells are starved of their substrate, many nutrient transporters are induced. These undergo rapid endocytosis and redirection of their intracellular trafficking when their substrate becomes available again. The discovery that some of these transporters also act as receptors, or transceptors, suggests that at least part of the sophisticated controls governing the trafficking of these proteins has to do with their signaling function rather than with control of transport. In yeast, the general amino acid permease Gap1 mediates signaling (...) to the protein kinase A pathway. Its endocytic internalization and intracellular trafficking are subject to amino acid control. Other nutrient transceptors controlling this signal transduction pathway appear to be subject to similar trafficking regulation. Transporters with complex regulatory control have also been suggested to function as transceptors in other organisms. Hence, precise regulation of intracellular trafficking in nutrient transporters may be related to the need for tight control of nutrient‐induced signaling. (shrink)

Glial cells play a central role in the development and function of complex nervous systems. Drosophila is an excellent model organism for the study of mechanisms underlying neural development, and recent attention has been focused on the differentiation and function of glial cells. We now have a nearly complete description of glial cell organization in the embryo, which enables a systematic genetic analysis of glial cell development. Most glia arise from neural stem cells that originate in the neurogenic (...) ectoderm. The bifurcation of glial and neuronal fates is under the control of the glial promoting factor glial cells missing. Differentiation is propagated through the regulation of several transcription factors. Genes have been discovered affecting the terminal differentiation of glia, including the promotion glial–neuronal interactions and the formation of the blood–nerve barrier. Other roles of glia are being explored, including their requirement for axon guidance, neuronal survival, and signaling. BioEssays 23:877–887, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Cell shape and cell contacts are determined by transmembrane receptor‐mediated associations of the cytoskeleton with specific extracellular matrix proteins and with ligands on the surface of adjacent cells. The cytoplasmic domains of these microfilament‐membrane associations at the adherens junction sites, also Iocalize a variety of regulatory molecules involved in signal transduction and gene regulation. The stimulation of cells with soluble polypeptide factors leads to rapid changes in cell shape and microfilament component organization. In addition, this stimulation also (...) activates the phosphoinositide signaling pathway. Recently, a linkage between actin‐binding proteins and the phosphoinositide signaling pathway, was discovered. It is Suggested that by the association with the second messenger system, and/or by controlling the localization of regulatory molecules, the cytoskeleton may regulate gene expression. (shrink)

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control of (...) gene expression. An age‐related decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. (shrink)

The Drosophila tracheal system is a branched tubular structure that supplies air to target tissues. The elaborate tracheal morphology is shaped by two linked inductive processes, one involving the choice of cell fates, and the other a guided cell migration. We will describe the molecular basis for these processes, and the allocation of cell fate decisions to four temporal hierarchies. First, tracheal placodes are specified within the embryonic ectoderm. Subsequently, branch fates are allocated within the tracheal placodes, (...) prior to migration. Localized presentation of the FGF ligand, Branchless, to tracheal cells that express the FGF receptor, Breathless, guides migration. Once cell migration is initiated, distinct cell fates are determined within each migrating branch. Finally, inhibitory feedback mechanisms ensure the correct assignment of these fates. Tracheal cell fate choices are determined by signaling cascades triggered by signals emanating from the tracheal cells, as well as by ligands produced by adjacent tissues. BioEssays 22:219–226, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Growth factor receptor tyrosine kinases (RTKs), such as the fibroblast growth factor receptor (FGFR), play a major role in how cells communicate with their environment. FGFR signaling is crucial for normal development, and its misregulation in humans has been linked to developmental abnormalities and cancer. The precise molecular mechanisms by which FGFRs transduce extracellular signals to effect specific biologic responses is an area of intense research. Genetic analyses in model organisms have played a central role in our evolving understanding (...) of these signal transduction cascades. Genetic studies in the nematode C. elegans have contributed to our knowledge of FGFR signaling by identifying genes involved in FGFR signal transduction and linking their gene products together into signaling modules. This review will describe FGFR-mediated signal transduction in C. elegans and focus on how these studies have contributed to our understanding of how FGFRs orchestrate the assembly of intracellular signaling pathways. BioEssays 23:1120–1130, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Planar cell polarity (PCP)‐signaling and associated tissue polarization are evolutionarily conserved. A well documented feature of PCP‐signaling in vertebrates is its link to centriole/cilia positioning, although the relationship of PCP and ciliogenesis is still debated. A recent report in Drosophila established that Frizzled (Fz)‐PCP core signaling has an instructive input to polarized centriole positioning in non‐ciliated Drosophila wing epithelia as a PCP read‐out. Here, we review the impact of this observation in the context of recent descriptions (...) of the relationship(s) of core Fz‐PCP signaling and cilia/centriole positioning in epithelial and non‐epithelial cells. All existing data are consistent with a model where Fz‐PCP signaling functions upstream of centriole/cilia positioning, independent of ciliogenesis. The combined data sets indicate that the Fz‐Dsh PCP complex is instructive for centriole/ciliary positioning via an actin‐based mechanism. Thereby, centriole/cilia/centrosome positioning can be considered an evolutionarily conserved readout and common downstream effect of PCP‐signaling from flies to mammals. (shrink)

Both Notch and NFκB signaling pathways are well‐known for regulating proliferation, differentiation and apoptosis. Recent studies have presented several lines of evidence supporting an integration of the Notch and NFκB signaling pathways in differentiation/maturation of a diverse range of cell types. It is notable that Notch and NFκB signaling pathways share many common features: (i) both are activated by common stimuli such as TNF‐α and hypoxia, (ii) activated Notch (NICD) and NFκB mediate transcription by regulating corepressors (...) such as SMRT/N‐COR, and (iii) both regulate similar target genes such as Hes‐1 and IκBα. This review expands on how the collaboration between these pathways may play an important role in the CNS. We will speculate on the mechanisms by which Notch and NFκB signaling may collaborate to regulate stem cell renewal and differentiation during brain development and function. BioEssays 29:1039–1047, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The JNK signaling pathway is involved in regulation of many cellular events, including growth control, transformation and programmed cell death (apoptosis). The role of JNK activation in apoptosis is highly controversial, being suggested to have a pro‐apoptotic, anti‐apoptotic or no role in this process. It appears that the JNK pathway functions in a cell‐type and stimulus‐dependent manner and its different components can sometimes play opposing roles in apoptosis. Recent studies reveal that the effect of JNK activation on (...) apoptosis depends on the activity of other signaling pathways like the NF‐κB pathway. Here we propose a model that can explain how activation of the JNK pathway “breaks the brake” on apoptosis, thereby regulating, but not initiating the apoptotic process. BioEssays 25:17–24, 2003. © 2002 Wiley Periodicals, Inc. (shrink)