Many bacteria that cause disease have the capacity to enter into and live within eukaryotic cells such as epithelial cells and macrophages. The mechanisms used by these organisms to achieve and maintain this intracellular lifestyle vary considerably, but most mechanisms involve subversion and exploitation of host cell functions. Entry into non‐phagocytic cells involves triggering host signal transduction mechanisms to induce rearrangement of the host cytoskeleton, thereby facilitating bacterial uptake. Once inside the host cell, intracellular pathogens either remain within membrane (...) bound inclusions or escape to the cytoplasm. Those living in the cytoplasm can further pirate the host actin system, using actin as a mechanism to facilitate movement within and between host cells. Organisms remaining within the vacuole have specialized mechanisms for intracellular survival and growth which involve additional communication with the host cell. Some of the processes involved in the various steps of facultative intracellular parasitism are discussed in the context of subverting the host cell cytoskeleton and signal transduction pathways for bacterial benefit. (shrink)

One of the earliest structural changes observed in cells in response to many extracellular factors is membrane ruffling: the formation of motile cell surface protrusions containing a meshwork of newly polymerized actin filaments. It is becoming clear that actin reorganization is an integral part of early signal transduction pathways, and that many signalling molecules interact with the actin cytoskeleton. The small GTP‐binding protein Rac is a key regulator of membrane ruffling, and proteins that can regulate Rac activity, such (...) as Bcr, are likely to act on this signalling pathway. In addition, several previously characterized signal transducing molecules are implicated in the membrane‐ruffling response, including Ras, the adaptor protein Grb2, phosphatidyl inositol 3‐kinase, phospholipase A2 and phorbol ester‐responsive proteins. Changes in polyphosphoinositide metabolism and intracellular Ca2+ levels may also play a role. A number of actin‐binding and organizing proteins localize to membrane ruffles and are potential targets for these signal transducing molecules. (shrink)

Embryonic development and adult tissue homeostasis are controlled through activation of intracellular signal transduction pathways by extracellular growth factors. In the past, signal transduction has largely been regarded as a linear process. However, more recent data from large‐scale and high‐throughput experiments indicate that there is extensive cross‐talk between individual signaling cascades leading to the notion of a signaling network. The behavior of such complex networks cannot be predicted by simple intuitive approaches but requires sophisticated models and computational (...) simulations. The purpose of such models is to generate experimentally testable hypotheses and to find explanations for unexpected experimental results. Here, we discuss the need for, and the future impact of, mathematical models for exploring signal transduction in different biological contexts such as for example development. BioEssays 30:1110–1125, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

A better understanding of how schistosomes exploit host nutrients, neuro‐endocrine hormones and signalling pathways for growth, development and maturation may provide new insights for improved interventions in the control of schistosomiasis. This paper describes recent advances in the identification and characterisation of schistosome tyrosine kinase and signalling pathways. It discusses the potential intervention value of insulin signalling, which may play an important role in glucose uptake and carbohydrate metabolism in schistosomes, providing the nutrients essential for parasite growth, development (...) and, notably, female fecundity. Significant progress has also been made in the characterisation of other schistosome growth factor receptors, such as transforming growth factor beta receptor and epidermal growth factor receptor, and in our understanding of their roles in the host‐parasite molecular dialogue and parasite development. The use of parasite signal transduction components as novel vaccine or drug targets may prove invaluable in prevention, treatment and control strategies to combat schistosomiasis. (shrink)

Cytokine receptors fall into two basic classes: those with their own intrinsic protein tyrosine kinase (PTK) domain, and those lacking a PTK domain. Nonetheless, PTK activity plays a fundamental role in the signal transduction processes lying downstream of both classes of receptor. It now seems likely that many of those cytokine receptors that lack their own PTK domain use members of the JAK family of PTKs to propagate their intracellular signals. Moreover, the involvement of the JAK kinases in a (...) newly defined pathway which links membrane receptors directly to the activation of nuclear genes, via latent cytoplasmic transcription factors known as STATs (for Signal Transducers and Activators of Transcription), appears to be a theme common to cytokine receptors of both classes. (shrink)

Taste cells respond to a wide variety of chemical stimuli: certain ions are perceived as salty (Na+) or sour (H+); other small molecules are perceived as sweet (sugars) and bitter (alkaloids). Taste has evolutionary value allowing animals to respond positively (to sweet carhohydrates and salty NaCl) or aversively (to bitter poisons and corrosive acids). Recently, some of the proteins involved in taste transduction have been cloned. Several different G proteins have been identified and cloned from taste tissue: gustducin is (...) a taste cell specific G protein closely related to the transducins. Work is under way to clone additional components of the taste transduction pathways. The combination of electrophysiology, biochemistry and molecular biology is being used to characterize taste receptor cells and their sensory transduction mechanisms. (shrink)

Insulin resistance is thought to be the primary defect in the pathophysiology of type 2 diabetes. Thus, understanding the cellular mechanisms of insulin action may contribute significantly to developing new treatments for this disease. Although the effects of insulin on glucose and lipid metabolism are well documented, gaps remain in our understanding of the precise molecular mechanisms of signal transduction for the hormone. One potential clue to understanding the unique cellular effects of insulin may lie in the compartmentalization of (...) signaling molecules and metabolic enzymes. We review this evidence, and speculate on how PI-3 kinase-independent and -dependent signaling pathways both diverge from the insulin receptor and converge at discrete targets to insure the specificity of insulin action. BioEssays 23:215–222, 2001. © 2001 John Wiley & Sons, Inc. (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)

The molecular cloning of new neuroactive growth factors and their receptors has greatly enhanced our understanding of important interactions among receptors and singnaling molecules. These studies have begun to illuminate some of the mechanisms that allow for specificity in neuronal signaling. Model cell systems, such as the PC‐12 pheochromocytoma cell line, express receptors for these different neurotirophic factors, leading to comparisons of signaling pathways for these factors. Upon binding their ligands, these receptors undergo phosphorylation on tyrosine residues, which directs (...) their interaction with signaling proteins containing src homology (SH2) domains, sequences that mediate associations with tyrosine‐phosphorylated proteins. These SH2 proteins translate the tyrosine kinase activity of receptors into downstream events that result in the specific cellular response. Investigations such as these have revealed that molecular specificity in signaling pathways may arise from combinatorial diversity in interactions between receptors and key regulatory proteins. (shrink)

For almost 30 years the ion channel that initiates the ON visual pathway in vertebrate vision has remained elusive. Recent findings now indicate that the pathway, which begins with unbinding of glutamate from the metabotropic glutamate receptor 6 (mGluR6), ends with the opening of the transient receptor potential (TRP)M1 cation channel. As a component of the mGluR6 signal transduction pathway, mutations in TRPM1 would be expected to cause congenital stationary night blindness (CSNB), and several such mutations have already been (...) identified in CSNB families. Furthermore, expression of TRPM1 in both the retina and skin raises the possibility that a genetic link exists between certain types of visual and skin disorders. (shrink)

Planar cell polarity (PCP), the alignment of cells within 2D tissue planes, involves a set of core molecular regulators highly conserved between animals and cell types. These include the transmembrane proteins Frizzled (Fz) and VanGogh and the cytoplasmic regulators Dishevelled (Dsh) and Prickle. It is widely accepted that this core forms part of a ‘PCP pathway’ for signal transduction, which can affect cell morphology through activation of an evolutionary ancient regulatory module involving Rho family GTPases and Myosin II, and/or (...) the JNK kinase cascade. We have re‐examined the evidence for interactions between the proposed PCP pathway components, and question the placing of the cell morphology regulators in the same pathway as the PCP core. While Fz and Dsh are clearly involved in both PCP and Rho‐based cell morphology regulation, available evidence cannot currently discriminate whether these processes are linked mechanistically by a shared Fz/Dsh population, or pass by two distinct pathways. (shrink)

Ubiquitination of protein species in regulating signal transduction pathways is universally accepted as of fundamental importance for normal development, and defects in this process have been implicated in the progression of many human diseases. One pathway that has received much attention in this context is transforming growth factor‐beta (TGF‐β) signalling, particularly during the regulation of epithelial‐mesenchymal transition (EMT) and tumour progression. While E3‐ubiquitin ligases offer themselves as potential therapeutic targets, much remains to be unveiled regarding mechanisms that culminate (...) in their regulation. With this in mind, the focus of this review highlights the regulation of the ubiquitination pathway and the significance of a recently described group of NEDD4 E3‐ubiquitin ligase isoforms in the context of TGF‐β pathway regulation. Moreover, we now broaden these observations to incorporate a growing number of protein isoforms within the ubiquitin ligase superfamily as a whole, and discuss their relevance in defining a new ‘iso‐ubiquitinome’. (shrink)

Despite its small size, profilin is an amazingly diverse and sophisticated protein whose precise role in cells continues to elude the understanding of researchers 15 years after its discovery. Its ubiquity, abundance and necessity for life in more evolved organisms certainly speaks for its exterme importance in cell function. So far, three ligands for profilin have been well‐characterized in vitro: actin monomers, membrane polyphosphoinositides and poly‐L‐proline. In the years following its discovery, profilin's role in vivo progressed from that of a (...) simple actin‐binding protein which inhibits actin polymerization, to one which, as an important regulator of the cytoskeleton, can even promote actin polymerization under the appropriate circumstances. In addition, interactions with components of the phosphatidylinositol cycle and the RAS pathway in yeast implicate profilin as an important link through which the actin cytoskeleton is able to communicate with major signaling pathways. (shrink)

Signaling by the Epidermal Growth Factor Receptor (EGFR) and related ErbB family receptor tyrosine kinases can be deregulated in human malignancies as the result of mutations in the genes that encode these receptors. The recent identification of EGFR mutations that correlate with sensitivity and resistance to EGFR tyrosine kinase inhibitors in lung and colon tumors has renewed interest in such activating mutations. Here we review current models for ligand stimulation of receptor dimerization and for activation of receptor signaling by receptor (...) dimerization. In the context of these models, we discuss ErbB receptor mutations that affect ligand binding and those that cause constitutive receptor phosphorylation and signaling as a result of constitutive receptor dimerization. We discuss mutations in the cytoplasmic regions that affect enzymatic activity, substrate specificity and coupling to effectors and downstream signaling pathways. Finally, we discuss how emergent mechanisms of ErbB receptor mutational activation could impact the search for clinically relevant ErbB receptor mutations. BioEssays 29:558–565, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Adapter molecules in a variety of signal transduction systems link receptors to a limited number of commonly used downstream signaling pathways. During T‐cell development and mature T‐cell effector function, a multichain receptor (the pre‐T‐cell antigen receptor or the T‐cell antigen receptor) activates several protein tyrosine kinases. Receptor and kinase activation is linked to distal signaling pathways (PLC‐γ1 activation, Ca2+ influx, PKC activation and Ras/Erk activation) via the adapter protein LAT (Linker for Activation of T cells). Structure/function studies (...) of LAT including expression of selected LAT point mutations in vivo reveals that these multiple pathways are integrated at the level of the LAT adapter. These studies suggest that similar levels of control may be found in other systems where adapter molecules are known to have important functions. BioEssays 26:61–67, 2004. Published 2003 Wiley Periodicals, Inc. (shrink)

Identification of Pygopus in Drosophila as a dedicated component of the Wg (fly homolog of mammalian Wnt) signaling cascade initiated many inquiries into the mechanism of its function. Surprisingly, the nearly exclusive role for Pygopus in Wg signal transduction in flies is not seen in mice, where Pygopus appears to have both Wnt‐related and Wnt‐independent functions. This review addresses the initial findings of Pygopus as a Wg/Wnt co‐activator in light of recent data from both fly and mammalian studies. We (...) compare and contrast the developmental phenotypes of pygopus mutants to those characterized for known Wg/Wnt transducers and explore the data regarding a role for mammalian Pygopus 2 in tumorigenesis. We further analyze the roles of the two conserved domains of Pygopus proteins in transcription, and propose a model for the molecular mechanism of Pygopus function in both Wg/Wnt signaling and Wnt‐independent transcriptional regulation. BioEssays 30:448–456, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Cellular circuits have positive and negative feedback loops that allow them to respond properly to noisy external stimuli. It is intriguing that such feedback loops exist in many cases in a particular form of coupled positive and negative feedback loops with different time delays. As a result of our mathematical simulations and investigations into various experimental evidences, we found that such coupled feedback circuits can rapidly turn on a reaction to a proper stimulus, robustly maintain its status, and immediately turn (...) off the reaction when the stimulus disappears. In other words, coupled feedback loops enable cellular systems to produce perfect responses to noisy stimuli with respect to signal duration and amplitude. This suggests that coupled positive and negative feedback loops form essential signal transduction motifs in cellular signaling systems. BioEssays 29: 85–90, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

Autophagy and YAP1‐WWTR1/TAZ signalling are tightly linked in a complex control system of forward and feedback pathways which determine different cellular outcomes in differing cell types at different time‐points after perturbations. Here we extend our previous experimental and modelling approaches to consider two possibilities. First, we have performed additional mathematical modelling to explore how the autophagy‐YAP1 crosstalk may be controlled by posttranslational modifications of components of the pathways. Second, since analogous contrasting results have also been reported for autophagy (...) as a regulator of other transduction pathways engaged in tumorigenesis (Wnt/β‐catenin, TGF‐β/Smads, NF‐kB or XIAP/cIAPs), we have considered if such discrepancies may be explicable through situations involving competing pathways and feedback loops in different cell types, analogous to the autophagy‐YAP/TAZ situation. Since distinct posttranslational modifications dominate those pathways in distinct cells, these need to be understood to enable appropriate cell type‐specific therapeutic strategies for cancers and other diseases. (shrink)

Signal transduction pathways constructed around a core module of three consecutive protein kinases, the most distal being a member of the extracellular signal‐regulated kinase (ERK) family, are ubiquitous among eukaryotes. Recent work has defined two cascades activated preferentially by the inflammatory cytokines TNF‐α and IL‐1‐β, as well as by a wide variety of cellular stresses such as UV and ionizing radiation, hyperosmolarity, heat stress, oxidative stress, etc. One pathway converges on the ERK subfamily known as the ‘stress activated’ (...) protein kinases (SAPKs, also termed Jun N‐terminal kinases, JNKs), whereas the second pathway recruits the p38 kinases. Upstream inputs are diverse, and include small GTPases (primarily Rac and Cdc42; secondarily Ras) acting through mammalian homologs of the yeast Ste20 kinase, other kinase subfamilies (e.g. GC kinase) and ceramide, a putative second messenger for certain TNF‐α actions. These two cascades signal cell cycle delay, cellular repair or apoptosis in most cells, as well as activation of immune and reticuloendothelial cells. (shrink)

Signal transduction pathways are largely conserved throughout the animal kingdom. The repertoire of pathways is limited and each pathway is used in different intercellular signaling events during the development of a given animal. For example, Wnt signaling is recruited, sometimes redundantly with other molecular pathways, in four cell specification events during Caenorhabditis elegans vulva development, including the activation of vulval differentiation. Strikingly,a recent study finds that Wnts act to repress vulval differentiation in the nematode Pristionchus pacificus,1 (...) demonstrating evolutionary flexibility in the use of intercellular signaling pathways. BioEssays 27:765–769, 2005. © 2005 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)

The precise orchestration of two opposing protein complexes – one in the cytoplasm (β‐catenin destruction complex) and the other at the plasma membrane (LRP6 signaling complex) – is critical for controlling levels of the transcriptional co‐factor β‐catenin, and subsequent activation of the Wnt/β‐catenin signal transduction pathway. The Wnt pathway component Axin acts as an essential scaffold for the assembly of both complexes. How the β‐catenin destruction and LRP6 signaling complexes are modulated following Wnt stimulation remains controversial. A recent study (...) in Science by He and coworkers reveals an underlying logic for Wnt pathway control in which Axin phosphorylation toggles a switch between the active and inactive states. This mini‐review focuses on this and two other recent studies that provide insight into the initial signaling events triggered by Wnt exposure. We emphasize regulation of the β‐catenin destruction and LRP6 signaling complexes and propose a framework for future work in this area. (shrink)

The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in spite of (...) the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels. (shrink)

Throughout 1994 remarkable progress was made with molecular and genetic studies on signal transduction pathways of photomorphogenesis, the lightdependent development of plants. Analysis of Arabidopsis DET and COP genes suggests that they are involved in suppression of photomorphogenic development in the dark and that this is then reversed by light. Studies with COP1 indicate that this is achieved by redistribution of COP1 from the nucleus, in the dark, to the cytosol in the light(1). Overexpression of COP1 in the (...) light, however, was able to partially suppress photomorphogenic development, confirming its role as a light‐inactivatable repressor(2). Evidence also suggests that some of the COP gene products may interact directly to form a large complex(3). (shrink)

The recent publication by Wylie et al. is reviewed, demonstrating that the p53 protein regulates the movement of transposons. While this work presents genetic evidence for a piRNA‐mediated p53 interaction with transposons in Drosophila and zebrafish, it is herein placed in the context of a decade or so of additional work that demonstrated a role for p53 in regulating transposons and other repetitive elements. The line of thought in those studies began with the observation that transposons damage DNA and p53 (...) regulates DNA damage. The presence of transposon movement can increase the rate of evolution in the germ line and alter genes involved in signal transduction pathways. Transposition can also play an important role in cancers where the p53 gene function is often mutated. This is particularly interesting as recent work has shown that de‐repression of repetitive elements in cancer has important consequences for the immune system and tumor microenvironment. (shrink)

Adequate reprogramming of cellular metabolism in response to stresses or suboptimal growth conditions involves a myriad of coordinated changes that serve to promote cell survival. As protein synthesis is an energetically expensive process, its regulation under stress is of critical importance. Reprogramming of messenger RNA (mRNA) translation involves well‐understood stress‐activated kinases that target components of translation initiation machinery, resulting in the robust inhibition of general translation and promotion of the translation of stress‐responsive proteins. Translational arrest of mRNAs also results in (...) the accumulation of transcripts in cytoplasmic foci called stress granules. Recent studies focus on the key roles of transfer RNA (tRNA) in stress‐induced translational reprogramming. These include stress‐specific regulation of tRNA pools, codon‐biased translation influenced by tRNA modifications, tRNA miscoding, and tRNA cleavage. In combination, signal transduction pathways and tRNA metabolism changes regulate translation during stress, resulting in adaptation and cell survival. This review examines molecular mechanisms that regulate protein synthesis in response to stress. (shrink)

Passage through the cell cycle requires the successive activation of different cyclin‐dependent protein kinases (CDKs). These enzymes are controlled by transient associations with cyclin regulatory subunits, binding of inhibitory polypeptides and reversible phosphorylation reactions. To promote progression towards DNA replication, CDK/cyclin complexes phosphorylate proteins required for the activation of genes involved in DNA synthesis, as well as components of the DNA replication machinery. Subsequently, a different set of CDK/cyclin complexes triggers the phosphorylation of numerous proteins to promote the profound structural (...) reorganizations that accompany the entry of cells into mitosis. At present, much research is focused on elucidating the links between CDK/cyclin complexes and signal transduction pathways controlling cell growth, differentiation and death. In future, a better understanding of the cell cycle machinery and its deregulation during oncogenesis may provide novel opportunities for the diagnostic and therapeutic management of cancer and other proliferation‐related diseases. (shrink)

The biochemical mechanism by which the phytochrome family of plant sensory photoreceptors transmit perceived informational light signals downstream to transduction pathway components is undetermined. The recent sequencing of the entire genome of the cyanobacterium Synechocystis, however, has revealed a protein that has an NH2‐terminal domain with striking sequence similarity to the photosensory NH2‐terminal domain of the phytochromes, and a COOH‐terminal domain strongly related to the transmitter histidine kinase module of bacterial two‐component sensors. The Synechocystis protein is capable of autocatalytic (...) chromophore ligation and exhibits photoreversible light‐absorption changes analogous to the phytochromes, indicating its capacity to function as an informational photoreceptor. Together with earlier observations that the COOH‐terminal domains of the plant phytochromes also have sequence similarity to the histidine kinases, these data suggest that the cyanobacteria utilize photoregulated histidine kinases as a sensory system and that the plant phytochromes may be evolutionary descendants of these photoreceptors. (shrink)

Lysophosphatidic acid (LPA) is a lipid mediator with a wide variety of biological actions, particularly as an inducer of cell proliferation, migration and survival. LPA binds to specific G‐protein‐coupled receptors and thereby activates multiple signal transduction pathways, including those initiated by the small GTPases Ras, Rho, and Rac. LPA signaling has been implicated in such diverse processes as wound healing, brain development, vascular remodeling and tumor progression. Knowledge of precisely how and where LPA is produced has long proved (...) elusive. Excitingly, it has recently been discovered that LPA is generated from precursors by ‘autotaxin’, a once enigmatic exo‐phosphodiesterase implicated in tumor cell motility. Exogenous phospholipases D can also produce LPA, which may contribute to their toxicity. Here we review recent progress in our understanding of LPA bioactivity, signaling and synthesis. BioEssays 26:870–881, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Modularity has become a central and remarkably useful concept in evolutionary developmental biology, offering an explanation of how independent, interacting units make possible developmental events and evolutionary changes. These modules exist at several different levels of organization, from genes to signal transduction pathways to cell populations. Cell populations, which are multicellular modules, provide an opportunity both to clarify our notion of modularity and to reexamine such central concepts as cell-to-cell communication. Rosine Chandebois’s work on “cell sociology” is reframed (...) in the language of modularity in order to show how groups of cells maintain their collective identity during development and how signaling information from the group’s environment is received by the constituent cells. In a “test case” for our account of multicellular modules, we consider the vertebrate neural crest, a migratory cell population made up of several subpopulations. The neural crest proves yet again to be a complex case, showing the importance of taking into account both developmental and evolutionary transformations of multicellular modules. (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)

Plants growing in temperate regions are able to survive freezing temperatures from −5° to −30°C, depending on the species, through a process known as cold acclimation. In the last decade much work has been done on the molecular mechanisms of low temperature (LT) signal transduction and cold acclimation. Mutant studies and microarray analyses have revealed C-Repeat binding factor (CBF) -dependent and -independent signaling pathways in plants. Experimental evidence suggests the existence of ‘potential LT sensors’ but as yet there (...) is no direct proof. A number of signal transducers such as various kinases/phosphatases have been demonstrated but the signal transduction pathways have not been elucidated. An understanding of the molecular basis of the signaling process, however, is of potential practical application. Designing new strategies to improve cold tolerance in crop varieties could increase the plant productivity and also expand the area under cultivation. BioEssays 27:1048–1059, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The dynamic structure and composition of lipid membranes need to be tightly regulated to control the vast array of cellular processes from cell and organelle morphology to protein‐protein interactions and signal transduction pathways. To maintain membrane integrity, sense‐and‐response systems monitor and adjust membrane lipid composition to the ever‐changing cellular environment, but only a relatively small number of control systems have been described. Here, we explore the emerging role of the ubiquitin‐proteasome system in monitoring and maintaining membrane lipid composition. (...) We focus on the ER‐resident RNF145 E3 ubiquitin ligase, its role in regulating adiponectin receptor 2 (ADIPOR2), its lipid hydrolase substrate, and the broader implications for understanding the homeostatic processes that fine‐tune cellular membrane composition. (shrink)

Synapsins I and II are a family of synaptic vesicle‐associated phosphoproteins involved in the short‐term regulation of neurotransmitter release. In this review, we discuss a working model for the molecular mechanisms by which the synapsins act. We propose that synapsin I links synaptic vesicles to actin filaments in the presynaptic nerve terminal and that these interactions are modulated by the reversible phosphorylation of synapsin I through various signal transduction pathways. The high degree of homology between the synapsins suggests (...) that some of the functional properties of synapsin I are also shared by synapsin II. (shrink)

Amino-terminal heteroacylation has been identified in retinal proteins including recoverin and α subunit of G-protein, transducin. The tissue-specific modification seems to mediate not only a proteinmembrane interaction but also a specific protein-protein interaction. The mechanism generating the heterogeneity and its physiological role are still unclear, but an interesting idea for the latter postulates a fine regulation of the signal transduction pathway by distinct N-acyl groups.

The regulatory properties of the neurospecific, type I adenylyl cyclase and its distribution within brain have suggested that this enzyme may be important for neuroplasticity. To address this issue, the murine, Ca2+ -stimulated adenylyl cyclase (type I), was inactivated by targeted mutagenesis. Ca2+ -stimulated adenylyl cyclase activity was reduced 40% to 60% in the hippocampus, neocortex, and cerebellum. Long term potentiation in the CA1 region of the hippocampus from mutants was perturbed relative to controls. Both the initial slope and maxim (...) um extent of changes in synaptic response were reduced. Although mutant mice learned to find a hidden platform normally in the Morris water task, they did not display a preference for the region where the platform had been when it was removed. The behavioral phenotype of these mice is very similar to that exhibited by mice which have been surgically lesioned in the hippocampus. These results indicate that disruption of the gene for the type I adenylyl cyclase produces changes in spatial memory and indicate that the cAMP signal transduction pathway may play an important role for synaptic plasticity. (shrink)

Adaptors are proteins of multi‐modular structure without enzymatic activity. Their capacity to organise large, temporary protein complexes by linking proteins together in a regulated and selective fashion makes them of outstanding importance in the establishment and maintenance of specificity and efficiency in all known signal transduction pathways. This review focuses on the structural and functional characterisation of adaptors involved in tyrosine kinase (TK) signalling. TK‐linked adaptors can be distinguished by their domain composition and binding specificities. However, such structural (...) classifications have proven inadequate as indicators of functional roles. A better way to understand the logic of signalling networks might be to look at functional aspects of adaptor proteins such as signalling specificity, negative versus positive contribution to signal propagation, or their position in the signalling hierarchy. All of these functions are dynamic, suggesting that adaptors have important regulatory roles rather than acting only as stable linkers in signal transduction. BioEssays 28: 465–479, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

During development one mechanism for generating different cell types is asymmetric cell division, by which a cell divides and contributes different factors to each of its daughter cells. Asymmetric cell division occurs through out the eukaryotic kingdom, from yeast to humans. Many asymmetric cell divisions occur in a defined orientation. This implies a cellular mechanism for sensing direction, which must ultimately lead to differences in gene expression between two daughter cells. In this review, we describe two classes of molecules: regulatory (...) factors that are differentially expressed upon asymmetric cell division, and components of a signal transduction pathway that may define cell polarity. The lin‐11 and mec‐3 genes of C. elegans, the Isl‐1 gene of mammals and the HO gene of yeast, encode regulatory factors that determine cell type of one daughter after asymmetric cell division. The CDC24 and CDC42 genes of yeast affect both bud positioning and orientation of mating projections, and thus may define a general cellular polarity. We speculate that molecules such as Cdc24 and Cdc42 may regulate expression of genes such as lin‐11, mec‐3, Isl‐1 and HO upon asymmetric cell division. (shrink)

Cyclic adenosine monophosphate (cAMP) and cAMP‐dependent protein kinase A (PKA) are evolutionary conserved molecules with a well‐established position in the complex network of signal transduction pathways. cAMP/PKA‐mediated signaling pathways are implicated in many biological processes that cooperate in organ development including the motility, survival, proliferation and differentiation of epithelial cells. Cell surface polarity, here defined as the anisotropic organisation of cellular membranes, is a critical parameter for most of these processes. Changes in the activity of cAMP/PKA elicit (...) a variety of effects on intracellular membrane dynamics, including membrane sorting and trafficking. One of the most intriguing aspects of cAMP/PKA signaling is its evolutionary conserved abundance on the one hand and its precise spatial–temporal actions on the other. Here, we review recent developments with regard to the role of cAMP/PKA in the regulation of intracellular membrane trafficking in relation to the dynamics of epithelial surface domains. BioEssays 30:146–155, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Members of the transforming growth factor beta (TGFβ) family are pleiotropic cytokines with key roles in tissue morphogenesis and growth. TGFβ1, TGFβ2 and TGFβ3 are abundant in mammalian reproductive tissues, where development and cyclic remodelling continue in post‐natal and adult life. Potential roles for TGFβ have been identified in gonad and secondary sex organ development, spermatogenesis and ovarian function, immunoregulation of pregnancy, embryo implantation and placental development. However, better tools must now be employed to map more precisely essential functions and (...) the regulatory networks governing their activity. Gene ablation and transgenic models are expected to provide novel insights into distinct physiological activities for each TGFβ isoform in normal reproductive function and reproductive pathologies. It is also necessary to consider the mechanisms controlling TGFβ activation from latent precursor forms, and receptor and binding protein expression. Smad intracellular signalling circuitry and modulation by environmental stimuli through cross‐talk with other signal transduction pathways will further constrain TGFβ action. This review examines existing evidence for TGFβ1, TGFβ2 and TGFβ3 regulation of male and female reproductive biology, and highlights prospects for future research. BioEssays 24:904–914, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

It has generally been observed that cells grow to a certain size before they divide. In the last few years, the PI3K signal transduction pathway has emerged as one of the main signaling routes utilized by cells to control their increase in size. Here we focus on two components of this pathway, PKB and S6K, and briefly review the experiments that initially uncovered their roles in cell size control. In addition, we discuss a number of recent observations suggesting that (...) the generic models used to describe this pathway to date may have been oversimplified. Indeed, recent observations in Drosophila and mouse support a more complex interaction between these signaling components in development. Finally, we have utilized two contemporary studies involving PKB‐ and S6K‐deficient mice as a paradigm to underscore the importance of cell size and to accurately delineate the connections between signaling pathways for human disease, such as diabetes mellitus. BioEssays 24:65–71, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

The mouse t-complex, located on chromosome 17, contains genes known to influence male, but not female, fertility. Although some t-complex genes are recessive lethals, t-chromosomes are maintained in the population by transmission ratio distortion. When male mice heterozygous for the t-chromosome mate with wild-type females, most offspring will possess the t-chromosome, indicating a link between t-complex genes and sperm function. Several proteins coded for by t-complex genes have been localised in the sperm flagellum, suggesting roles relating to motility. Another t-complex (...) protein appears able to regulate the adenylyl cyclase/cAMP signal transduction pathway, known to play an important role in capacitation. Defective motility and/or failure to capacitate (“switch on”) would result in poorly fertile or infertile spermatozoa. Given the existence of human homologues for many genes in the t-complex and the prevalence of “male factor” infertility, information obtained about the t-complex not only will provide insight into basic biological mechanisms but may be of future clinical relevance as well. BioEssays 21:304–312, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Mammalian oocytes exhibit a series of cell cycle transitions that coordinate the penultimate events of meiosis with the onset of embryogenesis at fertilization. The execution of these cell cycle transitions, at G2/M of meiosis‐I and metaphase/anaphase of meiosis I and II, involve both biosynthetic and post‐translational modifications that directly modulate centrosome and microtubule behavior. Specifically, somatic cells alter the signal transduction pathways in the oocyte and influence the expression of maturation promoting factor (MPF) and cytostatic factor (CSF) activity (...) through a microtubule‐dependent mechanism. The regulation of the oocytes' cell cycle machinery by hormone‐mediated somatic cell signals, involving both positive and negative stimuli, ensures that meiotic cell cycle progression is synchronized with the earliest pivotal events of mammalian reproduction. (shrink)

Our understanding of neuronal migration has been advanced by multidisciplinary approaches. At the cellular level, tangential and radial modes of neuronal migration contribute to different populations of neurons and have differential dependence on glial cells. At the molecular level, extracellular guidance cues have been identified and intracellular signal transduction pathways are beginning to be revealed. Interestingly, mechanisms guiding axon projection and neuronal migration appear to be conserved with those for chemotactic leukocytes. BioEssays 24:821–827, 2002. © 2002 Wiley Periodicals, (...) Inc. (shrink)

Recent advances in research on iron metabolism have revealed the identity of a number of genes, signal transduction pathways, and proteins involved in iron regulation in mammals. The emerging paradigm is a coordination of homeostasis within a network of classical iron metabolic pathways and other cellular processes such as cell differentiation, growth, inflammation, immunity, and a host of physiologic and pathologic conditions. Iron, immunity, and infection are intricately linked and their regulation is fundamental to the survival of (...) mammals. The mutual dependence on iron by the host and invading pathogenic organisms elicits competition for the element during infection. While the host maintains mechanisms to utilize iron for its own metabolism exclusively, pathogenic organisms are armed with a myriad of strategies to circumvent these measures. This review explores iron metabolism in mammalian host, defense mechanisms against pathogenic microbes and the competitive devices of microbes for access to iron. (shrink)

Bioactive peptides are a group of diverse intercellular signalling molecules. Almost half a century of research on this topic has resulted in an enormous amount of data. In this essay, a general perspective to interpret all these data will be given. In classical endocrinology, neuropeptides were thought of as simple signalling molecules that each elicit one response. However, the fact that the total bioactive peptide signal is far from simple puts this view under pressure. Cells and tissues express many different (...) bioactive peptides and they are also able to respond to many different bioactive peptides, indicating that multiple receptors and signal transduction pathways are present in a single cell. Therefore, the authors suggest that the bioactive peptide signalling system should be regarded in the context of network and systems biology. Bioactive peptides can best be viewed as an extension of the protein interaction network that allows regulating and fine‐tuning the metabolism of the different cells and tissues in the body. The cell thus responds to the ‘peptidome’ instead of to a single peptide. The intracellular part of this signalling network consists of the various signalling transduction cascades. Recently, new systems biology approaches have emerged for the modelling of cell signalling. The network and systems biology approach is also able to shed new light on the evolution of intercellular signalling. (shrink)

The life cycle of Dictyostelium discoideum offers a unique opportunity to study signal transduction in eukaryotic cells at both the unicellular and multicellular levels of organization. Adding to the already extensive knowledge of the unicellular stages, classical and molecular genetics have begun to unravel transduction of signals controlling morphogenesis and behaviour (phototaxis and thermotaxis) in the multicellular ‘slug’ stage of the life cycle. Distributed over all seven genetic linkage groups are probably about 20, but possibly as many as (...) 55, genes of importance for slug behaviour. The encoded proteins appear from pharmacological studies and mutant phenotypes to govern transduction pathways involving the intracellular second messengers cyclic AMP, cyclic GMP, IP3 and Ca2+. Pathways from the photo‐ and thermoreceptors converge first with each other and thence, at the level of the second messengers, with those from extracellular tip activation (cyclic AMP) and inhibition (Slug Turning Factor and/or ammonia and/or adenosine) signals that control slug movement and morphogenesis. (shrink)

Neural cell adhesion molecules of the immunoglobulin superfamily are important components of the network of guidance cues and receptors that govern axon growth and guidance during development. For neural cell adhesion molecule L1, the combined application of human genetics, knockout mouse technology, and cell biology is providing fundamental insight into the role of L1 in mediating neuronal differentiation. Disease-causing mutations as well as mouse models of L1 disruption can now be used to examine the relevance of L1 binding specificities and (...) signal transduction pathways that have been observed in vitro. BioEssays 20:668–675, 1998.© 1998 John Wiley & Sons Inc. (shrink)

Neural cell adhesion molecules of the immunoglobulin superfamily are important components of the network of guidance cues and receptors that govern axon growth and guidance during development. For neural cell adhesion molecule L1, the combined application of human genetics, knockout mouse technology, and cell biology is providing fundamental insight into the role of L1 in mediating neuronal differentiation. Disease-causing mutations as well as mouse models of L1 disruption can now be used to examine the relevance of L1 binding specificities and (...) signal transduction pathways that have been observed in vitro. BioEssays 20:668–675, 1998.© 1998 John Wiley & Sons Inc. (shrink)