The role of calcium in ABA-induced gene expression and stomatal movements

There is much interest in the transduction pathways by which abscisic acid (ABA) regulates stomatal movements (ABA-turgor signalling) and by which this phytohormone regulates the pattern of gene expression in plant cells (ABA-nuclear signalling). A number of second messengers have been identified in both the ABA-turgor and ABA-nuclear signalling pathways. A major challenge is to understand the architecture of ABA-signalling pathways and to determine how the ABA signal is coupled to the appropriate response. We have investigated whether separate Ca2+-dependent and -independent ABA-signalling pathways are present in guard cells. Our data suggest that increases in [Ca2+]i are a common component of the guard cell ABA-turgor and ABA-nuclear signalling pathways. The effects of Ca2+ antagonists on ABA-induced stomatal closure and the ABA-responsive CDeT6-19 gene promoter suggest that Ca2+ is involved in both ABA-turgor signalling and ABA-nuclear signalling in guard cells. However, the sensitivity of these pathways to alterations in the external calcium concentration differ, suggesting that the ABA-nuclear and ABA-turgor signalling pathways are not completely convergent. Our data suggest that whilst Ca2+-independent signalling elements are present in the guard cell, they do not form a completely separate Ca2+-independent ABA-signalling pathway.     

A signal-switch hypothesis for cross-regulation of cytokine and TLR signalling pathways

The importance of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors in modulating signalling pathways downstream of other types of receptor is well established, but the mechanisms underlying this modulation are not known. Recent data suggest that calcium-dependent signalling downstream of ITAM-coupled receptors regulates the amplitude and functional outcomes of cytokine and TLR signalling. In this Opinion article, I describe a model whereby the intensity of ITAM-dependent signalling and the balance of calcium signals relative to other ITAM-mediated signalling pathways determines whether cellular responses to cytokines and TLR ligands are increased or inhibited. This model describes mechanisms that explain how ITAM-coupled receptors regulate heterologous signalling pathways.     

Insulin signalling: metabolic pathways and mechanisms for specificity.

Biological actions of insulin are mediated by the insulin receptor, a member of a large family of receptor tyrosine kinases (RTK). Signal transduction by the insulin receptor follows a paradigm for RTK signalling. Many intracellular signalling molecules contain multiple modular domains that mediate protein-protein interactions and participate in the formation of signalling complexes. Phosphorylation cascades are also a prominent feature of RTK signalling. Distal pathways are difficult to dissect because branching paths emerge from downstream effectors and several upstream inputs converge upon single branch points. Thus, insulin action is determined by complicated signalling networks rather than simple linear pathways. Interestingly, many signalling molecules downstream from the insulin receptor are also activated by a plethora of RTKs. Therefore, mechanisms that generate specificity are required. In this review we discuss recent advances in the elucidation of specific metabolic insulin signalling pathways related to glucose transport, one of the most distinctive biological actions of insulin. We also present examples of potential mechanisms underlying specificity in insulin signalling including interactions between multiple branching pathways, subcellular compartmentalization, tissue-specific expression of key effectors and modulation of signal frequency and amplitude.     

昆虫先天性免疫信号通路研究进展

昆虫体内形成了强大的免疫防御系统,其被各种微生物攻击时能依靠病原相关分子模式识别蛋白对感染进行区分和激活体内信号通路诱导如抗菌肽之类的效应分子.昆虫体内控制先天性免疫的信号通路分别是:Toll通路、IMD通路和JAS/STAT通路,这3条通路在信号传递过程中存在协作,并且,这些通路与脊椎动物体内某些通路存在惊人相似、在免疫调控通路方面存在共同的进化起源.这揭示了先天性免疫在动物体内存在的普遍性和机体抵御病原感染的重要性.     

Beta-arrestin and casein kinase 1/2 define distinct branches of non-canonical WNT signalling pathways

Recent advances in understanding beta-catenin-independent WNT (non-canonical) signalling suggest an increasing complexity, raising the question of how individual non-canonical pathways are induced and regulated. Here, we examine whether intracellular signalling components such as beta-arrestin (beta-arr) and casein kinases 1 and 2 (CK1 and CK2) can contribute to determining signalling specificity in beta-catenin-independent WNT signalling to the small GTPase RAC-1. Our findings indicate that beta-arr is sufficient and required for WNT/RAC-1 signalling, and that casein kinases act as a switch that prevents the activation of RAC-1 and promotes other non-canonical WNT pathways through the phosphorylation of dishevelled (DVL, xDSH in Xenopus). Thus, our results indicate that the balance between beta-arr and CK1/2 determines whether WNT/RAC-1 or other non-canonical WNT pathways are activated.     

Synthetic biology: lessons from engineering yeast MAPK signalling pathways

All living cells respond to external stimuli and execute specific physiological responses through signal transduction pathways. Understanding the mechanisms controlling signalling pathways is important for diagnosing and treating diseases and for reprogramming cells with desired functions. Although many of the signalling components in the budding yeast Saccharomyces cerevisiae have been identified by genetic studies, many features concerning the dynamic control of pathway activity, cross‐talk, cell‐to‐cell variability or robustness against perturbation are still incompletely understood. Comparing the behaviour of engineered and natural signalling pathways offers insight complementary to that achievable with standard genetic and molecular studies. Here, we review studies that aim at a deeper understanding of signalling design principles and generation of novel signalling properties by engineering the yeast mitogen‐activated protein kinase (MAPK) pathways. The underlying approaches can be applied to other organisms including mammalian cells and offer opportunities for building synthetic pathways and functionalities useful in medicine and biotechnology.     

A Functional Genome-Wide In Vivo Screen Identifies New Regulators of Signalling Pathways during Early Xenopus Embryogenesis

Embryonic development requires exquisite regulation of several essential processes, such as patterning of tissues and organs, cell fate decisions, and morphogenesis. Intriguingly, these diverse processes are controlled by only a handful of signalling pathways, and mis-regulation in one or more of these pathways may result in a variety of congenital defects and diseases. Consequently, investigating how these signalling pathways are regulated at the molecular level is essential to understanding the mechanisms underlying vertebrate embryogenesis, as well as developing treatments for human diseases. Here, we designed and performed a large-scale gain-of-function screen in Xenopus embryos aimed at identifying new regulators of MAPK/Erk, PI3K/Akt, BMP, and TGF-β/Nodal signalling pathways. Our gain-of-function screen is based on the identification of gene products that alter the phosphorylation state of key signalling molecules, which report the activation state of the pathways. In total, we have identified 20 new molecules that regulate the activity of one or more signalling pathways during early Xenopus development. This is the first time that such a functional screen has been performed, and the findings pave the way toward a more comprehensive understanding of the molecular mechanisms regulating the activity of important signalling pathways under normal and pathological conditions.     

Wnt signalling during limb development

Wnts control a number of processes during limb development--from initiating outgrowth and controlling patterning, to regulating cell differentiation in a number of tissues. Interactions of Wnt signalling pathway components with those of other signalling pathways have revealed new mechanisms of modulating Wnt signalling, which may explain how different responses to Wnt signalling are elicited in different cells. Given the number of Wnts that are expressed in the limb and their ability to induce differential responses, the challenge will be to dissect precisely how Wnt signalling is regulated and how it controls limb development at a cellular level, together with the other signalling pathways, to produce the functional limb capable of coordinated precise movements.     

G protein-coupled receptor signalling and cross-talk: achieving rapidity and specificity

Activation of a given type of G protein-coupled receptor (GPCR) triggers a limited set of signalling events in a very rapid and specific manner. The classical paradigm of GPCR signalling was rather linear and sequential. Emerging evidence, however, has revealed that this is only a part of the complex signalling mediated by GPCR. Propagation of GPCR signalling involves cross-regulation of many but specific pathways, including cross-talks between different GPCRs as well as with other signalling pathways. Moreover, it is increasingly apparent that GPCRs can activate both heterotrimeric G protein-dependent and G protein-independent signalling pathways. In this review, we discuss how the signallings initiated by GPCRs achieve rapidity as well as specificity, and how the GPCRs can cross-regulate other specific signalling pathways at the same time. New concepts regarding GPCR signalling have been arising to address this issue, which include multiprotein signalling complex and signalling compartment in microdomain concepts that enable close colocalization or even contact among the proteins engaged in the specific signal transduction. The final outcome of a stimulation of GPCR will thus be the sum of its own specific set of intracellular signalling pathways it regulates.     

Regulatory Networks and Complex Interactions between the Insulin and Angiotensin II Signalling Systems: Models and Implications for Hypertension and Diabetes

The cross-talk between insulin and angiotensin II signalling pathways plays a significant role in the co-occurrence of diabetes and hypertension. We developed a mathematical model of the system of interactions among the biomolecules that are involved in the cross-talk between the insulin and angiotensin II signalling pathways. We have identified several feedback structures that regulate the dynamic behavior of the individual signalling pathways and their interactions. Different scenarios are simulated and dominant steady-state, dynamic and stability characteristics are revealed. The proposed mechanistic model describes how angiotensin II inhibits the actions of insulin and impairs the insulin-mediated vasodilation. The model also predicts that poor glycaemic control induced by diabetes contributes to hypertension by activating the renin angiotensin aystem.     

Nitric oxide and the enigma of cardiac hypertrophy

In pathological conditions associated with persistent increases in hemodynamic workload (old myocardial infarction, high blood pressure, valvular heart disease), a number of signalling pathways are activated in the heart, all of which promote hypertrophic growth of the heart, characterised at the cellular level by increases in individual cardiac myocyte size. Some of these pathways are required for a successful adaptation to cardiac injury. Other pathways are maladaptive, however, as they lead to progressive contractile dysfunction and heart failure. The free radical gas nitric oxide and natriuretic peptides, both of which are produced in the heart, have emerged as endogenous inhibitors of maladaptive hypertrophy signalling. Overall, it appears that cardiac hypertrophy is controlled by an interplay of pro- and antihypertrophic signalling networks. This delicate balance can tip towards adaptation or heart failure. In the future, patients living with cardiac disease may benefit from therapeutic strategies targeting maladaptive hypertrophy signalling pathways.     

Agonistic and Antagonistic Roles for TNIK and MINK in Non-Canonical and Canonical Wnt Signalling

Wnt signalling is a key regulatory factor in animal development and homeostasis and plays an important role in the establishment and progression of cancer. Wnt signals are predominantly transduced via the Frizzled family of serpentine receptors to two distinct pathways, the canonical ß-catenin pathway and a non-canonical pathway controlling planar cell polarity and convergent extension. Interference between these pathways is an important determinant of cellular and phenotypic responses, but is poorly understood. Here we show that TNIK (Traf2 and Nck-interacting kinase) and MINK (Misshapen/NIKs-related kinase) MAP4K signalling kinases are integral components of both canonical and non-canonical pathways in Xenopus. xTNIK and xMINK interact and are proteolytically cleaved in vivo to generate Kinase domain fragments that are active in signal transduction, and Citron-NIK-Homology (CNH) Domain fragments that are suppressive. The catalytic activity of the Kinase domain fragments of both xTNIK and xMINK mediate non-canonical signalling. However, while the Kinase domain fragments of xTNIK also mediate canonical signalling, the analogous fragments derived from xMINK strongly antagonize this signalling. Our data suggest that the proteolytic cleavage of xTNIK and xMINK determines their respective activities and is an important factor in controlling the balance between canonical and non-canonical Wnt signalling in vivo.     

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.     

Ras GTPases: integrins' friends or foes?

Integrins are cell-surface receptors that mediate and coordinate cellular responses to the extracellular matrix (ECM). Cellular signalling pathways can regulate cell adhesion by altering the affinity and avidity of integrins for ECM. The Ras family of small G proteins, which includes H-ras, R-ras and Rap, are important elements in cellular signalling pathways that control integrin function.     

Intracellular signalling cascades regulating innate immune responses to Mycobacteria: branching out from Toll-like receptors

Toll-like receptors (TLRs) recognize Mycobacterium tuberculosis (Mtb) or Mtb components and initiate mononuclear phagocyte responses that influence both innate and adaptive immunity. Recent studies have revealed the intracellular signalling cascades involved in the TLR-initiated immune response to mycobacterial infection. Although both TLR2 and TLR4 have been implicated in host interactions with Mtb, the relationship between specific mycobacterial molecules and various signal transduction pathways is not well understood. This review will discuss recent studies indicating critical roles for mycobacteria and mycobacterial components in regulation of mitogen-activated protein kinases and related signal transduction pathways that govern the outcome of infection and antibacterial defence. To better understand the roles of infection-induced signalling cascades in molecular pathogenesis, future studies are needed to clarify mechanisms that integrate the multiple signalling pathways that are activated by engagement of TLRs by both individual mycobacterial molecules and whole mycobacteria. These efforts will allow for the development of novel diagnostic and therapeutic modalities for tuberculosis that targets the intracellular signalling pathways permitting the replication of this nefarious pathogen.