Auxin cross-talk: integration of signalling pathways to control plant development

Plants sense and respond to endogenous signals and environmental cues to ensure optimal growth and development. Plant cells must integrate the myriad transduction events into a comprehensive network of signalling pathways and responses. The phytohormone auxin occupies a central place within this transduction network, frequently acting in conjunction with other signals, to co-ordinately regulate cellular processes such as division, elongation and differentiation. As a non-cell autonomous signal, auxin also interacts with other signalling pathways to regulate inter-cellular developmental processes. As part of this especially themed edition of Plant Molecular Biology, we will review examples of `cross-talk' between auxin and other signalling pathways. Given the current state of knowledge, we have deliberately focused our efforts reviewing auxin interactions with other phytohormone and light signalling pathways. We conclude by discussing how new genomic approaches and the Arabidopsis genome sequence are likely to impact this area of research in the future.     

Interactions between hormone and redox signalling pathways in the control of growth and cross tolerance to stress

The ability of plants to respond to a wide range of environmental stresses is highly flexible and finely balanced through the interaction of hormonal plant growth regulators and the redox signalling hub, which integrates information from the environment and cellular metabolism/physiology. Plant hormones produce reactive oxygen species (ROS) as second messengers in signalling cascades that convey information concerning changes in hormone concentrations and/or sensitivity to mediate a whole range of adaptive responses. Cellular redox buffering capacity that is determined largely by the abundance of ascorbate has a profound influence on the threshold at which hormone signalling is triggered and on the interactions between different hormones. Other antioxidants such as glutathione, glutaredoxins and thioredoxins are also central redox regulators of hormone signalling pathways. The complex network of cross-communication between oxidants and antioxidants in the redox signalling hub and the different hormone signalling pathways maximises productivity under stress-free situations and regulates plant growth, development, reproduction, programmed cell death and survival upon exposure to stress. This interactive network confers enormous regulatory potential because it allows plants to adapt to changing and often challenging conditions, while preventing boom or bust scenarios with regard to resources, ensuring that energy is produced and utilised in a safe and efficient manner.     

Multi-pathway network analysis of mammalian epithelial cell responses in inflammatory environments

Inflammation is a key physiological response to infection and injury and, although usually beneficial, it can also be damaging to the host. The liver is a prototypical example in this regard because inflammation helps to resolve liver injury, but it also underlies the aetiology of pathologies such as fibrosis and hepatocellular carcinoma. Liver cells sense their environment, including the inflammatory environment, through the activities of receptor-mediated signal transduction pathways. These pathways are organized in a complex interconnected network, and it is becoming increasingly recognized that cellular adaptations result from the quantitative integration of multi-pathway network activities, rather than isolated pathways causing particular phenotypes. Therefore comprehending liver cell signalling in inflammation requires a scientific approach that is appropriate for studying complex networks. In the present paper, we review our application of systems analyses of liver cell signalling in response to inflammatory environments. Our studies feature broad measurements of cell signalling and phenotypes in response to numerous experimental perturbations reflective of inflammatory environments, the data from which are analysed using Boolean and fuzzy logic models and regression-based methods in order to quantitatively relate the phenotypic responses to cell signalling network states. Our principal biological insight from these studies is that hepatocellular carcinoma cells feature uncoupled inflammatory and growth factor signalling, which may underlie their immune evasion and hyperproliferative properties.     

Boning up on glypicans—opportunities for new insights into bone biology

Bone formation is remarkable for the convergence in the activity of four major signalling pathways, the bone morphogenetic protein (BMP), fibroblast growth factor (FGF), hedgehog (HH) and wingless‐integrated (WNT) pathways. These pathways cooperate in morphogenetic, proliferative and differentiative processes that underpin the development, growth and repair of skeletal structures. They are regulated by pathway‐specific modulators and by another class of molecules, the glypicans. Glypicans are proteoglycans located on the cell surface, where they act as coreceptors to promote or inhibit signalling by ligands of the BMP, FGF, HH and WNT pathways, through protein–protein and protein–carbohydrate interactions. In this review, we discuss glypican structure, expression and function in the context of bone development and growth, with emphasis on the long bone growth plate where five of the six glypicans are expressed in overlapping patterns in the chondrogenic zone. Analyses of gene knockout models and the human conditions of Simpson–Golabi–Behmel syndrome and omodysplasia, which arise from mutations in glypican 3 (GPC3) and GPC6, respectively, highlight both subtle and striking effects of glypicans on bone growth. We draw attention to challenges and areas of opportunity, where the actions of glypicans on BMP, FGF, HH and WNT signalling might be profitably studied to help illuminate the complex interplay of signalling that drives bone growth. Copyright © 2013 John Wiley & Sons, Ltd.     

Multiple pathways to apoptosis.

Evidence from studies dealing with various aspects of the interdigitating network of proliferative signals supports the concept of multiple signalling pathways. Analogous to these, the concept of multiple pathways to apoptosis is introduced and discussed. Some of these pathways might not necessarily be under genetic control. They might be elicited by a perturbation at any point in the proliferative signalling network, for example by an imbalance in any of the substances involved directly or as second messengers. Diverse findings from recent reports on the induction of apoptosis by various means and in a variety of cell lines imply the presence of such multiple pathways, only one of which should accurately be described as genetic.     

Signal transduction pathways through cytoprotective, apoptotic and hypertrophic stimuli: a comparative study in adult cardiac myocytes

In response to pathophysiological stresses, cardiac myocytes undergo hypertrophic growth or apoptosis. Multiple signalling pathways have been implicated in these responses and among them, kinases such as mitogen‐activated protein kinases (MAPKs) and Akt. However, the distinction between signalling pathways originally believed to be specific for either hypertrophy, apoptosis or cell survival is fading. The existing data, coming from different experimental systems, often are conflicting. In this study, we sought to compare aspects of intracellular signalling activated by diverse stimuli in a single experimental system, adult rat cardiac myocytes. Furthermore, we assessed the role of these stimuli in eliciting a particular cell phenotype, i.e. whether they promote hypertrophy, cell survival or apoptosis. The results demonstrate that the hypertrophic agonist phenylephrine is the most potent activator of MAPKs/mitogen and stress‐ activated kinase MSK1, although its effect on Akt phosphorylation is relatively minor. The pro‐apoptotic concentration of H₂O₂ activates strongly both MAPKs and PI3K/Akt pathways. Insulin‐like growth factor‐1 has a minimal effect on phosphorylation of MAPKs/MSK1, but it is a potent activator of Akt. In conclusion, hypertrophic, pro‐survival or apoptotic stimuli operate through the same signalling pathways with different time course and amplitude of kinase activation. Thus, to determine the effect of different stimuli on cell fate, it is important to assess signalling pathways as a network and not as a single pathway. Copyright © 2011 John Wiley & Sons, Ltd.     

Pathway databases and tools for their exploitation: benefits,current limitations and challenges

In past years, comprehensive representations of cell signalling pathways have been developed by manual curation from literature, which requires huge effort and would benefit from information stored in databases and from automatic retrieval and integration methods. Once a reconstruction of the network of interactions is achieved, analysis of its structural features and its dynamic behaviour can take place. Mathematical modelling techniques are used to simulate the complex behaviour of cell signalling networks, which ultimately sheds light on the mechanisms leading to complex diseases or helps in the identification of drug targets. A variety of databases containing information on cell signalling pathways have been developed in conjunction with methodologies to access and analyse the data. In principle, the scenario is prepared to make the most of this information for the analysis of the dynamics of signalling pathways. However, are the knowledge repositories of signalling pathways ready to realize the systems biology promise? In this article we aim to initiate this discussion and to provide some insights on this issue.     

Updating the Wnt pathways

In the three decades since the discovery of the Wnt1 proto-oncogene in virus-induced mouse mammary tumours, our understanding of the signalling pathways that are regulated by the Wnt proteins has progressively expanded. Wnts are involved in an complex signalling network that governs multiple biological processes and cross-talk with multiple additional signalling cascades, including the Notch, FGF (fibroblast growth factor), SHH (Sonic hedgehog), EGF (epidermal growth factor) and Hippo pathways. The Wnt signalling pathway also illustrates the link between abnormal regulation of the developmental processes and disease manifestation. Here we provide an overview of Wnt-regulated signalling cascades and highlight recent advances. We focus on new findings regarding the dedicated Wnt production and secretion pathway with potential therapeutic targets that might be beneficial for patients with Wnt-related diseases.     

Arp2/3 and 'the shape of things to come'

The shape of plant cells is reliant upon an organised actin network. A series of recent publications have emphasised the central role played by the actin-nucleating Arp2/3 complex in plant growth. In animals and fungi, the Arp2/3 complex influences cell motility and morphogenesis through its ability to nucleate actin filaments locally in response to cell signalling pathways. There are potential parallels in the action and control of the Arp2/3 complex in plants and animals.     

Sequential and combinatorial inputs from Nodal, Delta2/Notch and FGF/MEK/ERK signalling pathways establish a grid-like organisation of distinct cell identities in the ascidian neural plate

The ascidian neural plate has a grid-like organisation, with six rows and eight columns of aligned cells, generated by a series of stereotypical cell divisions. We have defined unique molecular signatures for each of the eight cells in the posterior-most two rows of the neural plate - rows I and II. Using a combination of morpholino gene knockdown, dominant-negative forms and pharmacological inhibitors, we tested the role of three signalling pathways in defining these distinct cell identities. Nodal signalling at the 64-cell stage was found to be required to define two different neural plate domains - medial and lateral - with Nodal inducing lateral and repressing medial identities. Delta2, an early Nodal target, was found to then subdivide each of the lateral and medial domains to generate four columns. Finally, a separate signalling system along the anteroposterior axis, involving restricted ERK1/2 activation, was found to promote row I fates and repress row II fates. Our results reveal how the sequential integration of three signalling pathways - Nodal, Delta2/Notch and FGF/MEK/ERK - defines eight different sub-domains that characterise the ascidian caudal neural plate. Most remarkably, the distinct fates of the eight neural precursors are each determined by a unique combination of inputs from these three signalling pathways.     

Abiotic stress signalling pathways: specificity and cross-talk

Plants exhibit a variety of responses to abiotic stresses that enable them to tolerate and survive adverse conditions. As we learn more about the signalling pathways leading to these responses, it is becoming clear that they constitute a network that is interconnected at many levels. In this article, we discuss the 'cross-talk' between different signalling pathways and question whether there are any truly specific abiotic stress signalling responses.     

A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling

The mTOR (mammalian target of rapamycin) signalling pathway is a key regulator of cell growth and is controlled by growth factors and nutrients such as amino acids. Although signalling pathways from growth factor receptors to mTOR have been elucidated, the pathways mediating signalling by nutrients are poorly characterized. Through a screen for protein kinases active in the mTOR signalling pathway in Drosophila we have identified a Ste20 family member (MAP4K3) that is required for maximal S6K (S6 kinase)/4E-BP1 [eIF4E (eukaryotic initiation factor 4E)-binding protein 1] phosphorylation and regulates cell growth. Importantly, MAP4K3 activity is regulated by amino acids, but not the growth factor insulin and is not regulated by the mTORC1 inhibitor rapamycin. Our results therefore suggest a model whereby nutrients signal to mTORC1 via activation of MAP4K3.     

From individual Wnt pathways towards a Wnt signalling network

Wnt proteins play important roles during vertebrate and invertebrate development. They obviously have the ability to activate different intracellular signalling pathways. Based on the characteristic intracellular mediators used, these are commonly described as the Wnt/beta-catenin, the Wnt/calcium and the Wnt/Jun N-terminal kinase pathways (also called planar cell polarity pathway). In the past, these different signalling events were mainly described as individual and independent signalling branches. Here, we discuss the possibility that Wnt proteins activate a complex intracellular signalling network rather than individual pathways and suggest a graph representation of this network. Furthermore, we discuss different ways of how to predict the specific outcome of an activation of this network in a particular cell type, which will require the use of mathematical models. We point out that the use of deterministic approaches via the application of differential equations is suitable to model only small aspects of the whole network and that more qualitative approaches are possibly a suitable starting point for the prediction of the global behaviour of such large protein interaction networks.     

The sensing of nutritional status and the relationship to filamentous growth in Saccharomyces cerevisiae

Heterotrophic organisms rely on the ingestion of organic molecules or nutrients from the environment to sustain energy and biomass production. Non-motile, unicellular organisms have a limited ability to store nutrients or to take evasive action, and are therefore most directly dependent on the availability of nutrients in their immediate surrounding. Such organisms have evolved numerous developmental options in order to adapt to and to survive the permanently changing nutritional status of the environment. The phenotypical, physiological and molecular nature of nutrient-induced cellular adaptations has been most extensively studied in the yeast Saccharomyces cerevisiae. These studies have revealed a network of sensing mechanisms and of signalling pathways that generate and transmit the information on the nutritional status of the environment to the cellular machinery that implements specific developmental programmes. This review integrates our current knowledge on nutrient sensing and signalling in S. cerevisiae, and suggests how an integrated signalling network may lead to the establishment of a specific developmental programme, namely pseudohyphal differentiation and invasive growth.     

Light perception in plant disease defence signalling

Light is a predominant factor in the control of plant growth, development and stress responses. Many biotic stress responses in plants are therefore specifically adjusted by the prevailing light conditions. The plant cell is equipped with sophisticated light-sensing mechanisms that are localised inside and outside of the chloroplast and the nucleus. Recent progress has provided models of how the signalling pathways that are involved in light perception and in defence could operate and interact to form a plant defence network. Such a signalling network includes systems to sense light and regulate gene expression. Photo-produced H(2)O(2) and other reactive oxygen species in the cell also play an essential role in this regulatory network, controlling biotic and abiotic stress responses.     

Oridonin suppresses gastric cancer SGC-7901 cell proliferation by targeting the TNF-alpha/androgen receptor/TGF-beta signalling pathway axis

Statistics provided by GLOBOCAN list gastric cancer as the sixth most common, with a mortality ranking of third highest for the year 2020. In China, a herb called Rabdosia rubescens (Hemsl.) H.Hara, has been used by local residents for the treatment of digestive tract cancer for hundreds of years. Oridonin, the main ingredient of the herb, has a curative effect for gastric cancer, but the mechanism has not been previously clarified. This study mainly aimed to investigate the role of TNF-alpha/Androgen receptor/TGF-beta signalling pathway axis in mediating the proliferation inhibition of oridonin on gastric cancer SGC-7901 cells. MTT assay, cell morphology observation assay and fluorescence assay were adopted to study the efficacy of oridonin on cell proliferation. The network pharmacology was used to predict the pathway axis regulated by oridonin. Western blot assay was adopted to verify the TNF-α/Androgen receptor/TGF-β signalling pathway axis regulation on gastric cancer by oridonin. The results showed Oridonin could inhibit the proliferation of gastric cancer cells, change cell morphology and cause cell nuclear fragmentation. A total of 11signaling pathways were annotated by the network pharmacology, among them, Tumour necrosis factor alpha (TNF-α) signalling pathway, androgen receptor (AR) signalling pathway and transforming growth factor (TGF-β) signalling pathway account for the largest proportion. Oridonin can regulate the protein expression of the three signalling pathways, which is consistent with the results predicted by network pharmacology. These findings indicated that oridonin can inhibit the proliferation of gastric cancer SGC-7901 cells by regulating the TNF-α /AR /TGF-β signalling pathway axis.