The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Masaru Katoh - One of the best experts on this subject based on the ideXlab platform.
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wnt Signaling pathway and stem cell Signaling Network
Clinical Cancer Research, 2007Co-Authors: Masuko Katoh, Masaru KatohAbstract:WNT signals are transduced to the canonical pathway for cell fate determination, and to the noncanonical pathway for control of cell movement and tissue polarity. Canonical WNT signals are transduced through Frizzled family receptors and LRP5/LRP6 coreceptor to the beta-catenin Signaling cascade. Microtubule affinity-regulating kinase (PAR-1) family kinases, casein kinase I epsilon (CKI epsilon), and FRAT are positive regulators of the canonical WNT pathway, whereas APC, AXIN1, AXIN2, CKI alpha, NKD1, NKD2, beta TRCP1, beta TRCP2, ANKRD6, Nemo-like kinase (NLK), and peroxisome proliferator-activated receptor gamma (PPAR gamma) are negative regulators. Nuclear complex, consisting of T-cell factor/lymphoid enhancer factor, beta-catenin, BCL9/BCL9L, and PYGO, activates transcription of canonical WNT target genes such as FGF20, DKK1, WISP1, MYC, CCND1, and Glucagon (GCG). Noncanonical WNT signals are transduced through Frizzled family receptors and ROR2/RYK coreceptors to the Dishevelled-dependent (Rho family GTPases and c-jun NH(2)-terminal kinase) or the Ca(2+)-dependent (NLK and nuclear factor of activated T cells) Signaling cascades. WNT signals are context-dependently transduced to both pathways based on the expression profile of WNT, SFRP, WIF, DKK, Frizzled receptors, coreceptors, and the activity of intracellular WNT Signaling regulators. Epigenetic silencing and loss-of-function mutation of negative regulators of the canonical WNT pathway occur in a variety of human cancer. WNT, fibroblast growth factor (FGF), Notch, Hedgehog, and transforming growth factor beta/bone morphogenetic protein Signaling Network are implicated in the maintenance of tissue homeostasis by regulating self-renewal of normal stem cells as well as proliferation or differentiation of progenitor (transit-amplifying) cells. Breakage of the stem cell Signaling Network leads to carcinogenesis. Nonsteroidal anti-inflammatory drugs and PPAR gamma agonists with the potential to inhibit the canonical WNT Signaling pathway are candidate agents for chemoprevention. ZTM000990 and PKF118-310 are lead compounds targeted to the canonical WNT Signaling cascade. Anti-WNT1 and anti-WNT2 monoclonal antibodies show in vitro effects in cancer treatment. After the optimization, derivatives of small-molecule compound and human monoclonal antibody targeted to the WNT Signaling pathway could be used in cancer medicine.
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dysregulation of stem cell Signaling Network due to germline mutation snp helicobacter pylori infection epigenetic change and genetic alteration in gastric cancer
Cancer Biology & Therapy, 2007Co-Authors: Masaru KatohAbstract:Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable/fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacter pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NFkappaB Signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NFkappaB and TRAF6-MAP3K7-AP-1 Signaling cascades in epithelial and immune cells through lipopolysaccharide recognition by TLR2 or TLR4. IL-1beta, IL-6, IL-8, TNFalpha and IFNgamma are elevated in gastric mucosa with Helicobacter pylori infection. IL-6 and TNFalpha induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF, RhoA, JNK, PKC, NFAT, and NLK Signaling cascades. WNT-beta-catenin-TCF/LEF Signaling induces upregulation of MYC, CCND1, WISP1, FGF20, JAG1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NFkappaB Signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC, and NFAT Signaling cascades. Helicobacter pylori infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch Signaling, while DKK1 and SFRP1 inhibit WNT Signaling. Stem cell Signaling Network, consisting of WNT, Notch, FGF, Hedgehog and BMP Signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell Signaling Network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell Signaling molecules could be utilized for the personalized medicine.
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hedgehog Signaling pathway and gastrointestinal stem cell Signaling Network review
International Journal of Molecular Medicine, 2006Co-Authors: Yuriko Katoh, Masaru KatohAbstract:Hedgehog, BMP/TGFbeta, FGF, WNT and Notch Signaling pathways constitute the stem cell Signaling Network, which plays a key role in a variety of processes, such as embryogenesis, maintenance of adult tissue homeostasis, tissue repair during chronic persistent inflammation, and carcinogenesis. Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH) bind to PTCH1/PTCH or PTCH2 receptor to release Smoothened (SMO) signal transducer from Patched-dependent suppression. SMO then activates STK36 serine/threonine kinase to stabilize GLI family members and to phosphorylate SUFU for nuclear accumulation of GLI. Hedgehog Signaling activation leads to GLI-dependent transcriptional activation of target genes, such as GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1. GLI1-dependent positive feedback loop combined with PTCH1-dependent negative feedback loop gives rise to transient proliferation of Hedgehog target cells. Iguana homologs (DZIP1 and DZIP1L) and Costal-2 homologs (KIF7 and KIF27) are identified by comparative integromics. SHH-dependent parietal cell proliferation is implicated in gastric mucosal repair during chronic Helicobacter pylori infection. BMP-RUNX3 Signaling induces IHH expression in surface differentiated epithelial cells of stomach and intestine. Hedgehog signals from epithelial cells then induces FOXL1-mediated BMP4 upregulation in mesenchymal cells. Hedgehog Signaling is frequently activated in esophageal cancer, gastric cancer and pancreatic cancer due to transcriptional upregulation of Hedgehog ligands and epigenetic silencing of HHIP1/HHIP gene, encoding the Hedgehog inhibitor. However, Hedgehog Signaling is rarely activated in colorectal cancer due to negative regulation by the canonical WNT Signaling pathway. Hedgehog Signaling molecules or targets, such as SHH, IHH, HHIP1, PTCH1 and GLI1, are applied as biomarkers for cancer diagnostics, prognostics and therapeutics. Small-molecule inhibitors for SMO or STK36 are suitable to be used for treatment of Hedgehog-dependent cancer.
Siim Pauklin - One of the best experts on this subject based on the ideXlab platform.
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tgfb1 inhba homodimer nodal smad2 3 Signaling Network a pivotal molecular target in pdac treatment
Molecular Therapy, 2021Co-Authors: Mai Abdel Mouti, Siim PauklinAbstract:Pancreatic cancer remains a grueling disease that is projected to become the second-deadliest cancer in the next decade. Standard treatment of pancreatic cancer is chemotherapy, which mainly targets the differentiated population of tumor cells; however, it paradoxically sets the roots of tumor relapse by the selective enrichment of intrinsically chemoresistant pancreatic cancer stem cells that are equipped with an indefinite capacity for self-renewal and differentiation, resulting in tumor regeneration and an overall anemic response to chemotherapy. Crosstalk between pancreatic tumor cells and the surrounding stromal microenvironment is also involved in the development of chemoresistance by creating a supportive niche, which enhances the stemness features and tumorigenicity of pancreatic cancer cells. In addition, the desmoplastic nature of the tumor-associated stroma acts as a physical barrier, which limits the intratumoral delivery of chemotherapeutics. In this review, we mainly focus on the transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer/Nodal-SMAD2/3 Signaling Network in pancreatic cancer as a pivotal central node that regulates multiple key mechanisms involved in the development of chemoresistance, including enhancement of the stem cell-like properties and tumorigenicity of pancreatic cancer cells, mediating cooperative interactions between pancreatic cancer cells and the surrounding stroma, as well as regulating the deposition of extracellular matrix proteins within the tumor microenvironment.
Stuart L Schreiber - One of the best experts on this subject based on the ideXlab platform.
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finding new components of the target of rapamycin tor Signaling Network through chemical genetics and proteome chips
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Jing Huang, Heng Zhu, Stephen J Haggarty, David R Spring, Heejun Hwang, Fulai Jin, Michael Snyder, Stuart L SchreiberAbstract:Abstract The TOR (target of rapamycin) proteins play important roles in nutrient Signaling in eukaryotic cells. Rapamycin treatment induces a state reminiscent of the nutrient starvation response, often resulting in growth inhibition. Using a chemical genetic modifier screen, we identified two classes of small molecules, small-molecule inhibitors of rapamycin (SMIRs) and small-molecule enhancers of rapamycin (SMERs), that suppress and augment, respectively, rapamycin's effect in the yeast Saccharomyces cerevisiae. Probing proteome chips with biotinylated SMIRs revealed putative intracellular target proteins, including Tep1p, a homolog of the mammalian PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor, and Ybr077cp (Nir1p), a protein of previously unknown function that we show to be a component of the TOR Signaling Network. Both SMIR target proteins are associated with PI(3,4)P2, suggesting a mechanism of regulation of the TOR pathway involving phosphatidylinositides. Our results illustrate the combined use of chemical genetics and proteomics in biological discovery and map a path for creating useful therapeutics for treating human diseases involving the TOR pathway, such as diabetes and cancer. drug discovery drug target identification proteomics diabetes
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Signaling Network model of chromatin
Cell, 2002Co-Authors: Stuart L Schreiber, Bradley E BernsteinAbstract:We suggest that common principles underlie both cellular Signaling Networks and chromatin. To exemplify similarities, we focus on Signaling complexes that form at membrane receptors and on nucleosomes. Multiple signal-transducing modifications on side chain residues of receptor tyrosine kinases (RTKs) and histone proteins are used to create docking sites that facilitate proximal relations of enzymes and their substrates. We argue that multiple histone modifications, like RTK modifications, promote switch-like behavior and ensure robustness of the signal, and we compare this interpretation with the histone code hypothesis. This view provides insight into chromatin function and epigenetic inheritance.
Ronald D Vale - One of the best experts on this subject based on the ideXlab platform.
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in vitro membrane reconstitution of the t cell receptor proximal Signaling Network
Nature Structural & Molecular Biology, 2014Co-Authors: Ronald D ValeAbstract:Different kinases and phosphatases control the triggering of T-cell receptors. This Signaling Network is now reconstituted in vitro with CD3ζ, Lck, CD45, Csk and liposomes. Rigorous quantitative analyses reveal how the system is maintained in a quiescent state and how the kinase-phosphatase balance can be modulated by different events to allow activation in an ultrasensitive manner.
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in vitro membrane reconstitution of the t cell receptor proximal Signaling Network
Nature Structural & Molecular Biology, 2014Co-Authors: Enfu Hui, Ronald D ValeAbstract:T-cell receptor (TCR) phosphorylation is controlled by a complex Network that includes Lck, a Src family kinase (SFK), the tyrosine phosphatase CD45 and the Lck-inhibitory kinase Csk. How these competing phosphorylation and dephosphorylation reactions are modulated to produce T-cell triggering is not fully understood. Here we reconstituted this Signaling Network using purified enzymes on liposomes, recapitulating the membrane environment in which they normally interact. We demonstrate that Lck's enzymatic activity can be regulated over an ~10-fold range by controlling its phosphorylation state. By varying kinase and phosphatase concentrations, we constructed phase diagrams that reveal ultrasensitivity in the transition from the quiescent to the phosphorylated state and demonstrate that co-clustering TCR and Lck or detaching Csk from the membrane can trigger TCR phosphorylation. Our results provide insight into the mechanism of TCR Signaling as well as other Signaling pathways involving SFKs.
Michel De Vries - One of the best experts on this subject based on the ideXlab platform.
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a stress recovery Signaling Network for enhanced flooding tolerance in arabidopsis thaliana
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Elaine Yeung, Hans Van Veen, Divya Vashisht, Ana Luiza Sobral Pava, Maureen Hummel, Bianka Steffens, Anja Steffenheins, Margret Sauter, Tom Rankenberg, Michel De VriesAbstract:Abiotic stresses in plants are often transient, and the recovery phase following stress removal is critical. Flooding, a major abiotic stress that negatively impacts plant biodiversity and agriculture, is a sequential stress where tolerance is strongly dependent on viability underwater and during the postflooding period. Here we show that in Arabidopsis thaliana accessions (Bay-0 and Lp2-6), different rates of submergence recovery correlate with submergence tolerance and fecundity. A genome-wide assessment of ribosome-associated transcripts in Bay-0 and Lp2-6 revealed a Signaling Network regulating recovery processes. Differential recovery between the accessions was related to the activity of three genes: RESPIRATORY BURST OXIDASE HOMOLOG D, SENESCENCE-ASSOCIATED GENE113, and ORESARA1, which function in a regulatory Network involving a reactive oxygen species (ROS) burst upon desubmergence and the hormones abscisic acid and ethylene. This regulatory module controls ROS homeostasis, stomatal aperture, and chlorophyll degradation during submergence recovery. This work uncovers a Signaling Network that regulates recovery processes following flooding to hasten the return to prestress homeostasis.
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a stress recovery Signaling Network for enhanced flooding tolerance in arabidopsis thaliana
bioRxiv, 2018Co-Authors: Elaine Yeung, Hans Van Veen, Divya Vashisht, Ana Luiza Sobral Pava, Maureen Hummel, Bianka Steffens, Anja Steffenheins, Margret Sauter, Michel De Vries, Robert C SchuurinkAbstract:Abiotic stresses in plants are often transient and the recovery phase following stress removal is critical. Flooding, a major abiotic stress that negatively impacts plant biodiversity and agriculture, is a sequential stress where tolerance is strongly dependent on viability underwater and during the post-flooding period. Here we show that in Arabidopsis thaliana accessions (Bay-0 and Lp2-6), different rates of submergence recovery correlate with submergence tolerance and fecundity. A genome-wide assessment of ribosome-associated transcripts in Bay-0 and Lp2-6 revealed a Signaling Network regulating recovery processes. Differential recovery between the accessions was related to the activity of three genes: RESPIRATORY BURST OXIDASE HOMOLOG (RBOHD) , SENESCENCE-ASSOCIATED GENE113 (SAG113) and ORESARA1 (ORE1/NAC6) which function in a regulatory Network involving a reactive oxygen species (ROS) burst upon de-submergence and the hormones abscisic acid and ethylene. This regulatory module controls ROS homeostasis, stomatal aperture and chlorophyll degradation during submergence recovery. This work uncovers a Signaling Network that regulates recovery processes following flooding to hasten the return to pre-stress homeostasis.
