A5060617351- Protein Kinase Regulation and GTPase Signaling
- Fungal and yeast genetics research
- Enzyme Structure and Function
- Melanoma and MAPK Pathways
- PI3K/AKT/mTOR signaling in cancer
- Monoclonal and Polyclonal Antibodies Research
- Cell Adhesion Molecules Research
- Cellular transport and secretion
- Cell death mechanisms and regulation
- Endoplasmic Reticulum Stress and Disease
- Metabolism, Diabetes, and Cancer
- Enzyme function and inhibition
- Psoriasis: Treatment and Pathogenesis
- RNA and protein synthesis mechanisms
- Genetics, Aging, and Longevity in Model Organisms
- Signaling Pathways in Disease
- Wnt/β-catenin signaling in development and cancer
- Genetics and Neurodevelopmental Disorders
- Neuroscience and Neuropharmacology Research
- Fermentation and Sensory Analysis
- Neurogenesis and neuroplasticity mechanisms
- T-cell and B-cell Immunology
- NF-κB Signaling Pathways
- Ubiquitin and proteasome pathways
- Protein Structure and Dynamics
Kobe University
2013-2024
Institute of Macromolecular Chemistry
2017
Osaka City University
2002-2013
University of the Ryukyus
2001
The University of Tokyo
1978-1998
Cold Spring Harbor Laboratory
1984-1990
Harvard University
1987-1989
Osaka University
1981-1983
Kyoto University
1981
We have assessed the number of times gene sequence encoding constant regions mouse immunoglobulin heavy chains gamma1, gamma2a, and gamma3 are represented in genome by hybridization kinetic analysis. All three genes present at one copy each per haploid normal tissues myelomas producing IgM or IgG3. IgG1-producing myelomas, however, contain 1 gamma1 gamma2a 0.5 genome. IgG2b-producing IgG2a-producing In IgA, all gamma order to account for results we propose an allelic deletion model: (i) The...
Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for development inhibitors, partly owing to absence well-defined surface pockets suitable binding. Only recently, such have found crystal structures a unique conformation Ras⋅GTP. Here we report successful small-molecule inhibitors by an silico screen targeting pocket...
Phosphoinositide-specific phospholipase C (PI-PLC) plays a pivotal role in regulation of intracellular signal transduction from various receptor molecules. More than 10 members human PI-PLC isoforms have been identified and classified into three classes β, γ, δ, which are regulated by distinct mechanisms. Here we report identification novel class PI-PLC, named PLCε, is characterized the presence Ras-associating domain at its terminus CDC25-like N terminus. The PLCε specifically binds to...
Cloning and nucleotide sequence determination suggest that the rearranged gamma 1-chain gene in a 1-chain-producing myeloma a-pears to be formed by recombination between 5' flanking regions of 1- mu-chain genes undifferentiated cells. The site is distinct from putative J region novel we call S region. We have extended our previous model explains heavy-chain class switching two or more successive events.
Abstract Mutational activation of the ras proto-oncogenes is frequently found in skin cancers. However, nature downstream signaling pathways from Ras involved carcinogenesis remains poorly understood. Recently, we and others identified phospholipase C (PLC) ε as an effector Ras. Here have examined role PLCε de novo chemical by using mice whose genetically inactivated. PLCε−/− exhibit delayed onset markedly reduced incidence squamous tumors induced initiation with...
Ras family small GTPases assume two interconverting conformations, "inactive" state 1 and "active" 2, in their GTP-bound forms. Here, to clarify the mechanism of transition, we have carried out x-ray crystal structure analyses a series mutant H-Ras M-Ras complex with guanosine 5'-(beta,gamma-imido)triphosphate (GppNHp), representing various intermediate states transition. Crystallization H-RasT35S-GppNHp enables us solve first complete tertiary possessing surface pockets unseen 2 or...
The interaction between "switch I/effector domain" of Ha-Ras and the Ras-binding domain (RBD, amino acid 51-131) Raf-1 is essential for signal transduction. However, importance "activator (approximately corresponding to acids 26-28 40-49) "cysteine-rich region" (CRR, 152-184) have also been proposed. Here, we found that CRR interacts directly with independently RBD participation necessary efficient Ras-Raf binding. Furthermore, carrying mutations (N26G V45E) in activator failed bind CRR,...
Phospholipase Cepsilon (PLCepsilon) is a novel class of phosphoinositide-specific PLC characterized by possession CDC25 homology and Ras/Rap1-associating domains. We others have shown that human PLCepsilon translocated from the cytoplasm to plasma membrane activated direct association with Ras at its domain. In addition, translocation perinuclear region was induced upon Rap1.GTP. However, function domain remains be clarified. Here we show functions as guanine nucleotide exchange factor for...
Ras proteins undergo a series of posttranslational modifications that are critical for their cellular function. These necessary to anchor the membrane. Yeast Ras2 were purified with various degrees modification and examined ability activate effector, adenylyl cyclase. The farnesylated intermediate form had more than 100 times higher affinity cyclase unprocessed form. subsequent palmitoylation reaction little effect. In contrast, was required efficient membrane localization protein. results...
A Saccharomyces cerevisiae gene encoding adenylate cyclase has been analyzed by deletion and insertion mutagenesis to localize regions required for activation the Sa. RAS2 protein. The NH2-terminal 657 amino acids were found be dispensable activation. However, almost all 2-amino acid insertions in middle 600 residues comprising leucine-rich repeats deletions COOH-terminal 66 completely abolished protein, whereas mutations other generally had no effect. Chimeric cyclases constructed swapping...
The Rho family GTPase Rac1 has been implicated in the regulation of glucose uptake myoblast cell lines. However, no evidence for role provided by a mouse model. purpose this study is to test involvement insulin action skeletal muscle. Intravenous administration indeed elicited activation gastrocnemius muscle, suggesting signaling pathway. We then examined whether insulin-stimulated translocation facilitative transporter GLUT4 from its storage sites muscle sarcolemma depends on Rac1. show...
A Schizosaccharomyces pombe gene encoding adenylate cyclase has been cloned by cross-hybridization with the Saccharomyces cerevisiae gene. The protein encoded consists of 1692 amino acids and activity that cannot be activated Sa. RAS2 protein. Sc. a high degree homology (approximately 60%) catalytic domain precisely mapped gene-deletion analysis. 25-40% identity is observed throughout middle segments approximately 1000 residues both cyclases, large parts which are composed repetitions...
Ras small GTPases undergo dynamic equilibrium of two interconverting conformations, state 1 and 2, in the GTP-bound forms, where 2 is recognized by effectors, whereas physiological functions have been unknown. Limited information, such as static crystal structures (31)P NMR spectra, was available for study conformational dynamics. Here we determine solution structure dynamics multidimensional heteronuclear analysis an H-RasT35S mutant complex with guanosine 5'-(β, γ-imido)triphosphate...
Apc Min/+ mice, carrying an inactivated allele of the a denomatous polyposis coli gene, are widely used as animal model for human colorectal tumorigenesis, where tumor environment, such inflammation, is known to play critical role in progression. We previously demonstrated that phospholipase C (PLC)ε, effector Ras and Rap small GTPases, plays crucial two-stage skin chemical carcinogenesis using 12- O -tetradecanoyl-phorbor-13-acetate (TPA) promoter through augmentation TPA-induced...
An expressed gene for gamma 1 chain of MC 101 myeloma was cloned from a phage library containing partial EcoRI digests DNA. The DNA analyzed by restriction enzyme cleavage, Southern blot hybridization, R-loop formation, and nucleotide sequence determination. results indicate that the comprises at least four germline segments, namely variable-region gene, segment 5' flanking region mu (containing J regions), alpha with its regions. presence gene-flanking switch (S) (S region) side indicates...
GTP‐bound Ras adopts two interconverting conformations, “inactive” state 1 and “active” 2. However, the tertiary structure of wild‐type (WT) remains unsolved. Here we solve crystal structures H‐Ras WT together with its oncogenic G12V Q61L mutants. They assume open characterized by impaired interactions both Thr‐35 in switch I Gly‐60 II γ‐phosphate GTP possess surface pockets mutually different shapes unseen 2, a potential target for selective inhibitor development. Furthermore, they provide...
Previous studies have reported that insulin resistance plays an important role in the progression of atherosclerosis. However, relationship between and coronary plaque instability is not well established. The purpose this study was to assess characteristics identified by optical coherence tomography (OCT).This enrolled 155 consecutive patients undergoing percutaneous intervention. OCT image acquisitions were performed culprit lesions. Insulin using homeostasis model assessment (HOMA-IR)....
Mammalian Ras proteins regulate multiple effectors including Raf, Ral guanine nucleotide dissociation stimulator (RalGDS), and phosphoinositide 3-kinase. In the nematode Caenorhabditis elegans, LIN-45 Raf has been identified by genetic analyses as an effector of LET-60 Ras. To search for other in C. we performed a yeast two-hybrid screening LET-60-binding proteins. The two cDNA clones encoding phosphoinositide-specific phospholipase C (PI-PLC) with predicted molecular mass 210 kDa,...