Showing papers on "Signal transduction published in 2018"
TL;DR: Molecular understanding of the allosteric coupling between ligand binding and G protein or arrestin interaction is emerging from structures of several GPCRs crystallized in inactive and active states, spectroscopic data, and computer simulations.
Abstract: G protein-coupled receptors (GPCRs) mediate the majority of cellular responses to external stimuli. Upon activation by a ligand, the receptor binds to a partner heterotrimeric G protein and promotes exchange of GTP for GDP, leading to dissociation of the G protein into α and βγ subunits that mediate downstream signals. GPCRs can also activate distinct signaling pathways through arrestins. Active states of GPCRs form by small rearrangements of the ligand-binding, or orthosteric, site that are amplified into larger conformational changes. Molecular understanding of the allosteric coupling between ligand binding and G protein or arrestin interaction is emerging from structures of several GPCRs crystallized in inactive and active states, spectroscopic data, and computer simulations. The coupling is loose, rather than concerted, and agonist binding does not fully stabilize the receptor in an active conformation. Distinct intermediates whose populations are shifted by ligands of different efficacies underlie the complex pharmacology of GPCRs.
644 citations
TL;DR: Current insights into the structural plasticity of G PCR–G-protein and GPCR–arrestin complexes that underlies the regulation of the receptor’s intracellular signaling profile are summarized.
Abstract: G-protein-coupled receptors (GPCRs) relay numerous extracellular signals by triggering intracellular signaling through coupling with G proteins and arrestins. Recent breakthroughs in the structural determination of GPCRs and GPCR-transducer complexes represent important steps toward deciphering GPCR signal transduction at a molecular level. A full understanding of the molecular basis of GPCR-mediated signaling requires elucidation of the dynamics of receptors and their transducer complexes as well as their energy landscapes and conformational transition rates. Here, we summarize current insights into the structural plasticity of GPCR-G-protein and GPCR-arrestin complexes that underlies the regulation of the receptor's intracellular signaling profile.
561 citations
TL;DR: The role of AhR in the regulation of the immune response in the context of autoimmunity, infection, and cancer is discussed, as well as the potential opportunities and challenges of developing AhR-targeted therapeutics.
516 citations
TL;DR: The discovery of Y260 in α1 Na/K-ATPase as a Src-specific phosphorylation and binding site is discovered and it is suggested that the role of this regulation in control of Warburg effect and tumor growth may lead to Warburg phenotype in cancer.
Abstract: We report here the identification of α1 Na/K-ATPase as a major regulator of the proto-oncogene Src kinase and the role of this regulation in control of Warburg effect and tumor growth. Specifically, we discovered Y260 in α1 Na/K-ATPase as a Src-specific phosphorylation and binding site and that Y260 phosphorylation is required for Src-mediated signal transduction in response to a number of stimuli including EGF. As such, it enables a dynamic control of aerobic glycolysis. However, such regulation appears to be lost or attenuated in human cancers as the expression of Na/K-ATPase α1 was significantly decreased in prostate, breast and kidney cancers, and further reduced in corresponding metastatic lesions in patient samples. Consistently, knockdown of α1 Na/K-ATPase led to a further increase in lactate production and the growth of tumor xenograft. These findings suggest that α1 Na/K-ATPase works as a tumor suppressor and that a loss of Na/K-ATPase-mediated Src regulation may lead to Warburg phenotype in cancer.
509 citations
TL;DR: The processes whereby RTKs are activated under normal physiological conditions are reviewed and several mechanisms wherebyRTKs can be aberrantly activated in human cancers are discussed.
Abstract: Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.
497 citations
TL;DR: It is increasingly clear that within each T cell subset, IL-2 will signal within a framework of other signal transduction networks that together will shape the transcriptional and metabolic programs that determine T cell fate.
Abstract: The discovery of interleukin-2 (IL-2) changed the molecular understanding of how the immune system is controlled. IL-2 is a pleiotropic cytokine, and dissecting the signaling pathways that allow IL-2 to control the differentiation and homeostasis of both pro- and anti-inflammatory T cells is fundamental to determining the molecular details of immune regulation. The IL-2 receptor couples to JAK tyrosine kinases and activates the STAT5 transcription factors. However, IL-2 does much more than control transcriptional programs; it is a key regulator of T cell metabolic programs. The development of global phosphoproteomic approaches has expanded the understanding of IL-2 signaling further, revealing the diversity of phosphoproteins that may be influenced by IL-2 in T cells. However, it is increasingly clear that within each T cell subset, IL-2 will signal within a framework of other signal transduction networks that together will shape the transcriptional and metabolic programs that determine T cell fate.
438 citations
TL;DR: How extracellular ATP and P2 purinergic signalling can shape the tumour microenvironment to both promote and restrain tumour progression is described and the opportunities to harness nucleotide receptor signalling as an anticancer strategy are outlined.
Abstract: Modulation of the biochemical composition of the tumour microenvironment is a new frontier of cancer therapy. Several immunosuppressive mechanisms operate in the milieu of most tumours, a condition that makes antitumour immunity ineffective. One of the most potent immunosuppressive factors is adenosine, which is generated in the tumour microenvironment owing to degradation of extracellular ATP. Accruing evidence over the past few years shows that ATP is one of the major biochemical constituents of the tumour microenvironment, where it acts at P2 purinergic receptors expressed on both tumour and host cells. Stimulation of P2 receptors has different effects depending on the extracellular ATP concentration, the P2 receptor subtype engaged and the target cell type. Among P2 receptors, the P2X purinergic receptor 7 (P2X7R) subtype appears to be a main player in host–tumour cell interactions. Preclinical studies in several tumour models have shown that P2X7R targeting is potentially a very effective anticancer treatment, and many pharmaceutical companies have now developed potent and selective small molecule inhibitors of P2X7R. In this Review, we report on the multiple mechanisms by which extracellular ATP shapes the tumour microenvironment and how its stimulation of host and tumour cell P2 receptors contributes to determining tumour fate. In this Review, Di Virgilio et al. describe how extracellular ATP and P2 purinergic signalling can shape the tumour microenvironment to both promote and restrain tumour progression and outline the opportunities to harness nucleotide receptor signalling as an anticancer strategy.
422 citations
TL;DR: The role that is played by the TLR4 signaling pathway in the inflammatory response and its modulation by saturated and omega-3 polyunsaturated fatty acids is described.
Abstract: Obesity leads to an inflammatory condition that is directly involved in the etiology of cardiovascular diseases, type 2 diabetes mellitus, and certain types of cancer. The classic inflammatory response is an acute reaction to infections or to tissue injuries, and it tends to move towards resolution and homeostasis. However, the inflammatory process that was observed in individuals affected by obesity and metabolic syndrome differs from the classical inflammatory response in certain respects. This inflammatory process manifests itself systemically and it is characterized by a chronic low-intensity reaction. The toll-like receptor 4 (TLR4) signaling pathway is acknowledged as one of the main triggers of the obesity-induced inflammatory response. The aim of the present review is to describe the role that is played by the TLR4 signaling pathway in the inflammatory response and its modulation by saturated and omega-3 polyunsaturated fatty acids. Studies indicate that saturated fatty acids can induce inflammation by activating the TLR4 signaling pathway. Conversely, omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, exert anti-inflammatory actions through the attenuation of the activation of the TLR4 signaling pathway by either lipopolysaccharides or saturated fatty acids.
416 citations
TL;DR: This review article summarizes recent advances in the understanding of the Th17/Treg balance and its implications with respect to autoimmune disease.
Abstract: T helper type 17 (Th17) cells and pTreg cells, which share a common precursor cell (the naive CD4 T cell), require a common tumor growth factor (TGF)-β signal for initial differentiation. However, terminally differentiated cells fulfill opposite functions: Th17 cells cause autoimmunity and inflammation, whereas Treg cells inhibit these phenomena and maintain immune homeostasis. Thus, unraveling the mechanisms that affect the Th17/Treg cell balance is critical if we are to better understand autoimmunity and tolerance. Recent studies have identified many factors that influence this balance; these factors range from signaling pathways triggered by T cell receptors, costimulatory receptors, and cytokines, to various metabolic pathways and the intestinal microbiota. This review article summarizes recent advances in our understanding of the Th17/Treg balance and its implications with respect to autoimmune disease.
398 citations
TL;DR: This study indicates that both NPR1 and NPR3/NPR4 are bona fide SA receptors, but play opposite roles in transcriptional regulation of SA-induced defense gene expression.
388 citations
TL;DR: Adiponectin's anti-inflammatory and anti-apoptotic properties results in protection of the vasculature, heart, lung, and colon.
Abstract: Adipose tissue is now recognized as an important endocrine organ, capable of secreting a large number of endocrine factors which regulate a wide variety of physiological functions. Adiponectin is one such factor, secreted in large quantities primarily from adipose tissue. Adiponectin is posttranslationally modified from a 30-kDa monomeric protein into different multimers (low molecular weight or trimer, middle molecular weight or hexamer, and high molecular weight) and secreted into the circulation. Upon binding to its receptors, AdipoR1 and R2, adiponectin initiates a series of tissue-dependent signal transduction events, including phosphorylation of adenosine monophosphate (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK), and increased peroxisome proliferator-activated receptor alpha (PPARα) ligand activity. These signal transduction events are regulated by adaptor protein containing a pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif (APPL1), which binds directly to the intracellular regions of AdipoR1 and R2. AdipoR1 and R2 also possesses inherent ceramidase activity, resulting in a decrease in intracellular ceramide, a sphingolipid that has been implicated in insulin resistance, cell death, inflammation, and atherosclerosis. Adiponectin stimulates fatty acid oxidation in skeletal muscle and inhibits glucose production in the liver, resulting in an improvement in whole-body energy homeostasis. Adiponectin is also a classic anti-inflammatory agent, reducing inflammation in various cell types through AdipoR1 and R2 signaling mechanisms. Adiponectin's anti-inflammatory and anti-apoptotic properties results in protection of the vasculature, heart, lung, and colon. In this review, we provide a comprehensive overview of the discovery, protein structure, receptors, expression, regulation, and physiological functions of adiponectin. © 2017 American Physiological Society. Compr Physiol 8:1031-1063, 2018.
TL;DR: This review gives a short insight into the functional formation of these cytokine receptors and discusses both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by whichThese cytokines induce intracellular signaling and gene expression.
Abstract: Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of lymphocytes, myeloid cells, and non-hematopoietic cells. In T-cells, IL-4 induces the differentiation of naive CD4 T cells into Th2 cells, in B cells, IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation. This review gives a short insight into the functional formation of these cytokine receptors. I will discuss both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by which these cytokines induce intracellular signaling and gene expression. Work initiated in part by William (Bill) E. Paul on IL-4 some 30 years ago has now grown into a major building block of our current understanding of basic immunology and the immune response. This knowledge on IL-4 has growing clinical importance, as therapeutic approaches targeting the cytokine and its signal transduction are becoming a part of the clinical practice in treating allergic diseases. Just by reading the reference list of this short review, one can appreciate the enormous input Bill has had on shaping our understanding of the pathophysiology of allergic inflammation and in particular the role of IL-4 in this process.
TL;DR: In addition to the regulation of xenobiotic metabolism, numerous alternative functions have been characterized for the AhR since its discovery, which will be described in this review along with its endogenous functions as revealed by experiments performed on knock-out animals.
Abstract: The ageing suppressor α-klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of α-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, α-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of α-klotho is incompatible with its purported glycosidase activity. Thus, shed α-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling.
TL;DR: The molecular structure of c-Met and HGF and the mechanism through which their interaction activates the PI3K/AKT, Ras/MAPK, and Wnt signaling pathways are elaborate and the current therapeutic drugs targeted in primary tumors are introduced.
Abstract: c-Met is a receptor tyrosine kinase belonging to the MET (MNNG HOS transforming gene) family, and is expressed on the surfaces of various cells. Hepatocyte growth factor (HGF) is the ligand for this receptor. The binding of HGF to c-Met initiates a series of intracellular signals that mediate embryogenesis and wound healing in normal cells. However, in cancer cells, aberrant HGF/c-Met axis activation, which is closely related to c-Met gene mutations, overexpression, and amplification, promotes tumor development and progression by stimulating the PI3K/AKT, Ras/MAPK, JAK/STAT, SRC, Wnt/β-catenin, and other signaling pathways. Thus, c-Met and its associated signaling pathways are clinically important therapeutic targets. In this review, we elaborate on the molecular structure of c-Met and HGF and the mechanism through which their interaction activates the PI3K/AKT, Ras/MAPK, and Wnt signaling pathways. We also summarize the connection between c-Met and RON and EGFR, which are also receptor tyrosine kinases. Finally, we introduce the current therapeutic drugs that target c-Met in primary tumors, and their use in clinical research.
TL;DR: There is now ample evidence for a role of IL‐18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease, however,IL‐18 plays a very specific role in the pathogenesis of hemophagocytic syndromes also termed Macrophage Activation Syndrome.
Abstract: Initially described as an interferon (IFN)γ-inducing factor, interleukin (IL)-18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL-17-producing γδ T cells and macrophage activation. IL-18, a member of the IL-1 family, is similar to IL-1β for being processed by caspase 1 to an 18 kDa-biologically active mature form. IL-18 binds to its specific receptor (IL-18Rα, also known as IL-1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL-18Rβ chain. IL-18 then uses the same signaling pathway as IL-1 to activate NF-kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL-18 also binds to the circulating high affinity IL-18 binding protein (BP), such as only unbound free IL-18 is active. IL-18Rα may also bind IL-37, another member of the IL-1 family, but in association with the negative signaling chain termed IL-1R8, which transduces an anti-inflammatory signal. IL-18BP also binds IL-37 and this acts as a sink for the anti-inflammatory properties of IL-37. There is now ample evidence for a role of IL-18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL-18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain-of-function mutations, IL-18 circulates in the range of tens of nanograms/mL. HS is treated with the IL-1 Receptor antagonist (anakinra) but also specifically with IL-18BP. Systemic juvenile idiopathic arthritis or adult-onset Still's disease are also characterized by high serum IL-18 concentrations and are treated by IL-18BP.
TL;DR: In this paper, a review of NF-κB p65-mediated signaling is presented, followed by a discussion of strategies that directly target NF-Kb p65 in the context of chronic inflammation.
Abstract: The transcription factor NF-κB is a critical regulator of immune and inflammatory responses. In mammals, the NF-κB/Rel family comprises five members: p50, p52, p65 (Rel-A), c-Rel, and Rel-B proteins, which form homo- or heterodimers and remain as an inactive complex with the inhibitory molecules called IκB proteins in resting cells. Two distinct NF-κB signaling pathways have been described: 1) the canonical pathway primarily activated by pathogens and inflammatory mediators, and 2) the noncanonical pathway mostly activated by developmental cues. The most abundant form of NF-κB activated by pathologic stimuli via the canonical pathway is the p65:p50 heterodimer. Disproportionate increase in activated p65 and subsequent transactivation of effector molecules is integral to the pathogenesis of many chronic diseases such as the rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and even neurodegenerative pathologies. Hence, the NF-κB p65 signaling pathway has been a pivotal point for intense drug discovery and development. This review begins with an overview of p65-mediated signaling followed by discussion of strategies that directly target NF-κB p65 in the context of chronic inflammation.
TL;DR: Though quantification of these TLRs helps in correlating the magnitude of immune response exhibited by the animal, there are several internal, external, genetic and animal factors that affect their expression patterns that may lead to improper diagnosis during certain conditions.
Abstract: This review attempts to cover the implication of the toll-like receptors (TLRs) in controlling immune functions with emphasis on their significance, function, regulation and expression patterns. The tripartite TLRs are type I integral transmembrane receptors that are involved in recognition and conveying of pathogens to the immune system. These paralogs are located on cell surfaces or within endosomes. The TLRs are found to be functionally involved in the recognition of self and non-self-antigens, maturation of DCs and initiation of antigen-specific adaptive immune responses as they bridge the innate and adaptive immunity. Interestingly, they also have a significant role in immunotherapy and vaccination. Signals generated by TLRs are transduced through NFκB signaling and MAP kinases pathway to recruit pro-inflammatory cytokines and co-stimulatory molecules, which promote inflammatory responses. The excess production of these cytokines leads to grave systemic disorders like tumor growth and autoimmune disorders. Hence, regulation of the TLR signaling pathway is necessary to keep the host system safe. Many molecules like LPS, SOCS1, IRAK1, NFκB, and TRAF3 are involved in modulating the TLR pathways to induce appropriate response. Though quantification of these TLRs helps in correlating the magnitude of immune response exhibited by the animal, there are several internal, external, genetic and animal factors that affect their expression patterns. So it can be concluded that any identification based on those expression profiles may lead to improper diagnosis during certain conditions.
TL;DR: The data show that CAR signaling pathways cannot be predicted solely by the domains used to construct the receptor and that signal strength is a key determinant of T cell fate, and suggest that tailoring CAR design based on signal strength may lead to improved clinical efficacy and reduced toxicity.
Abstract: Chimeric antigen receptors (CARs) link an antigen recognition domain to intracellular signaling domains to redirect T cell specificity and function. T cells expressing CARs with CD28/CD3ζ or 4-1BB/CD3ζ signaling domains are effective at treating refractory B cell malignancies but exhibit differences in effector function, clinical efficacy, and toxicity that are assumed to result from the activation of divergent signaling cascades. We analyzed stimulation-induced phosphorylation events in primary human CD8+ CD28/CD3ζ and 4-1BB/CD3ζ CAR T cells by mass spectrometry and found that both CAR constructs activated similar signaling intermediates. Stimulation of CD28/CD3ζ CARs activated faster and larger-magnitude changes in protein phosphorylation, which correlated with an effector T cell-like phenotype and function. In contrast, 4-1BB/CD3ζ CAR T cells preferentially expressed T cell memory-associated genes and exhibited sustained antitumor activity against established tumors in vivo. Mutagenesis of the CAR CD28 signaling domain demonstrated that the increased CD28/CD3ζ CAR signal intensity was partly related to constitutive association of Lck with this domain in CAR complexes. Our data show that CAR signaling pathways cannot be predicted solely by the domains used to construct the receptor and that signal strength is a key determinant of T cell fate. Thus, tailoring CAR design based on signal strength may lead to improved clinical efficacy and reduced toxicity.
TL;DR: An overview is presented on the underlying mechanisms of the effects of SCFAs on both immune and endothelial cells, including HDACs, FFA2 and FFA3 receptors and GPR109A regulation of nuclear factor‐kappa B activation and mitogen‐activated protein kinase (MAPK) signaling pathways.
TL;DR: The mechanisms regulating eIF2α kinases, the role that uORFs play in translational control, and the impact that alteration of eIF1α phosphorylation by gene mutations or small molecule inhibitors can have on health and disease are highlighted.
Abstract: A central mechanism regulating translation initiation in response to environmental stress involves phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Phosphorylation of eIF2α causes inhibition of global translation, which conserves energy and facilitates reprogramming of gene expression and signaling pathways that help to restore protein homeostasis. Coincident with repression of protein synthesis, many gene transcripts involved in the stress response are not affected or are even preferentially translated in response to increased eIF2α phosphorylation by mechanisms involving upstream open reading frames (uORFs). This review highlights the mechanisms regulating eIF2α kinases, the role that uORFs play in translational control, and the impact that alteration of eIF2α phosphorylation by gene mutations or small molecule inhibitors can have on health and disease.
TL;DR: The data reveal that Rab29 is a master regulator of LRRK2, controlling its activation, localization, and potentially biomarker phosphorylation of a cluster of highly studied biomarkerosphorylation sites.
Abstract: Parkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase proteins including Rab29, within the effector-binding switch II motif. Previous work indicated that Rab29, located within the PARK16 locus mutated in Parkinson's patients, operates in a common pathway with LRRK2. Here, we show that Rab29 recruits LRRK2 to the trans-Golgi network and greatly stimulates its kinase activity. Pathogenic LRRK2 R1441G/C and Y1699C mutants that promote GTP binding are more readily recruited to the Golgi and activated by Rab29 than wild-type LRRK2. We identify conserved residues within the LRRK2 ankyrin domain that are required for Rab29-mediated Golgi recruitment and kinase activation. Consistent with these findings, knockout of Rab29 in A549 cells reduces endogenous LRRK2-mediated phosphorylation of Rab10. We show that mutations that prevent LRRK2 from interacting with either Rab29 or GTP strikingly inhibit phosphorylation of a cluster of highly studied biomarker phosphorylation sites (Ser910, Ser935, Ser955 and Ser973). Our data reveal that Rab29 is a master regulator of LRRK2, controlling its activation, localization, and potentially biomarker phosphorylation.
TL;DR: A state of “zero functional G” is achieved at the cellular level using HEK293 cells depleted by CRISPR/Cas9 technology of the Gs/q/12 families of Gα proteins, along with pertussis toxin-mediated inactivation of Gi/o.
Abstract: G protein-independent, arrestin-dependent signaling is a paradigm that broadens the signaling scope of G protein-coupled receptors (GPCRs) beyond G proteins for numerous biological processes. However, arrestin signaling in the collective absence of functional G proteins has never been demonstrated. Here we achieve a state of “zero functional G” at the cellular level using HEK293 cells depleted by CRISPR/Cas9 technology of the Gs/q/12 families of Gα proteins, along with pertussis toxin-mediated inactivation of Gi/o. Together with HEK293 cells lacking β-arrestins (“zero arrestin”), we systematically dissect G protein- from arrestin-driven signaling outcomes for a broad set of GPCRs. We use biochemical, biophysical, label-free whole-cell biosensing and ERK phosphorylation to identify four salient features for all receptors at “zero functional G”: arrestin recruitment and internalization, but—unexpectedly—complete failure to activate ERK and whole-cell responses. These findings change our understanding of how GPCRs function and in particular of how they activate ERK1/2.
TL;DR: It is indicated that SB ameliorated the TNBS-induced inflammatory response and intestinal epithelium barrier dysfunction through activating GPR109A and inhibiting the AKT and NF-κB p65 signaling pathways and provide a new theoretical basis for treatment of IBD.
TL;DR: The data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers and provide evidence for a critical dependence of mutant KRAS on SHp2 during carcinogenesis.
Abstract: The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors1. Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways1-7. Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro8. Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.
TL;DR: The role of JAK proteins in cancer biology, the most recent developments in targeting JAKs, and the central role they play in intracellular cross-talks with other signaling cascades are highlighted.
Abstract: Janus tyrosine kinase (JAK) family of proteins have been identified as crucial proteins in signal transduction initiated by a wide range of membrane receptors. Among the proteins in this family JAK2 has been associated with important downstream proteins, including signal transducers and activators of transcription (STATs), which in turn regulate the expression of a variety of proteins involved in induction or prevention of apoptosis. Therefore, the JAK/STAT signaling axis plays a major role in the proliferation and survival of different cancer cells, and may even be involved in resistance mechanisms against molecularly targeted drugs. Despite extensive research focused on the protein structure and mechanisms of activation of JAKs, and signal transduction through these proteins, their importance in cancer initiation and progression seem to be underestimated. This manuscript is an attempt to highlight the role of JAK proteins in cancer biology, the most recent developments in targeting JAKs, and the central role they play in intracellular cross-talks with other signaling cascades.
TL;DR: The structures of SOCS1 bound to its JAK1 target as well as in complex with elonginB and elonginC are presented, providing a molecular explanation for the potent JAK- inhibitory activity of SOCs1.
Abstract: The SOCS family of proteins are negative-feedback inhibitors of signalling induced by cytokines that act via the JAK/STAT pathway. SOCS proteins can act as ubiquitin ligases by recruiting Cullin5 to ubiquitinate signalling components; however, SOCS1, the most potent member of the family, can also inhibit JAK directly. Here we determine the structural basis of both these modes of inhibition. Due to alterations within the SOCS box domain, SOCS1 has a compromised ability to recruit Cullin5; however, it is a direct, potent and selective inhibitor of JAK catalytic activity. The kinase inhibitory region of SOCS1 targets the substrate binding groove of JAK with high specificity and thereby blocks any subsequent phosphorylation. SOCS1 is a potent inhibitor of the interferon gamma (IFNγ) pathway, however, it does not bind the IFNγ receptor, making its mode-of-action distinct from SOCS3. These findings reveal the mechanism used by SOCS1 to inhibit signalling by inflammatory cytokines.
TL;DR: An ideal therapeutic strategy for autoimmune diseases would be to selectively block the sTNF/TNFR1 signal through the administration of sT NF inhibitors, or using TNFR1 antagonists while keeping the TNFR2 signaling pathway intact.
Abstract: Tumor Necrosis Factor α (TNFα) is a pleiotropic cytokine which signals through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Emerging evidence has demonstrated that TNFR1 is ubiquitously expressed on almost all cells, while TNFR2 exhibits a limited expression, predominantly on regulatory T cells (Tregs). Additionally, the signaling pathway by sTNF via TNFR1 mainly triggers pro-inflammatory pathways, and mTNF binding to TNFR2 usually initiates immune modulation and tissue regeneration. TNFα plays a critical role in up-regulation or down-regulation of Treg activity. Deficiency in TNFR2 signaling is significant in various autoimmune diseases. An ideal therapeutic strategy for autoimmune diseases would be to selectively block the sTNF/TNFR1 signal through the administration of sTNF inhibitors, or using TNFR1 antagonists while keeping the TNFR2 signaling pathway intact. Another promising strategy would be to rely on TNFR2 agonists which could drive the expansion of Tregs and promote tissue regeneration. Design of these therapeutic strategies targeting the TNFR1 or TNFR2 signaling pathways holds promise for the treatment of diverse inflammatory and degenerative diseases.
TL;DR: It is shown that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs, which facilitates transfer of plasma constituents from ECs to the adipocyte.
TL;DR: The results suggest that the phytomelatonin regulation of stomatal closure is dependent on its receptor CAND2/PMTR1‐mediated H2O2 and Ca2+signaling transduction cascade.
Abstract: Melatonin has been detected in plants in 1995; however, the function and signaling pathway of this putative phytohormone are largely undetermined due to a lack of knowledge about its receptor. Here, we discovered the first phytomelatonin receptor (CAND2/PMTR1) in Arabidopsis thaliana and found that melatonin governs the receptor-dependent stomatal closure. The application of melatonin induced stomatal closure through the heterotrimeric G protein α subunit-regulated H2 O2 and Ca2+ signals. The Arabidopsis mutant lines lacking AtCand2 that encodes a candidate G protein-coupled receptor were insensitive to melatonin-induced stomatal closure. Accordingly, the melatonin-induced H2 O2 production and Ca2+ influx were completely abolished in cand2. CAND2 is a membrane protein that interacts with GPA1 and the expression of AtCand2 was tightly regulated by melatonin in various organs and guard cells. CAND2 showed saturable and specific 125 I-melatonin binding, with apparent Kd (dissociation constant) of 0.73 ± 0.10 nmol/L (r2 = .99), demonstrating this protein is a phytomelatonin receptor (PMTR1). Our results suggest that the phytomelatonin regulation of stomatal closure is dependent on its receptor CAND2/PMTR1-mediated H2 O2 and Ca2+ signaling transduction cascade.