A5067220105- Metabolism, Diabetes, and Cancer
- Growth Hormone and Insulin-like Growth Factors
- Pancreatic function and diabetes
- Protein Kinase Regulation and GTPase Signaling
- Cancer, Hypoxia, and Metabolism
- Receptor Mechanisms and Signaling
- Estrogen and related hormone effects
- Diabetes Management and Research
- Axon Guidance and Neuronal Signaling
- Diabetes and associated disorders
- Fungal and yeast genetics research
- Cytokine Signaling Pathways and Interactions
- Glycosylation and Glycoproteins Research
- Protein Structure and Dynamics
- Galectins and Cancer Biology
- Ion Transport and Channel Regulation
- Bioinformatics and Genomic Networks
- DNA Repair Mechanisms
- Fungal Biology and Applications
- Heart Rate Variability and Autonomic Control
- Luminescence and Fluorescent Materials
- Viral Infectious Diseases and Gene Expression in Insects
- Pituitary Gland Disorders and Treatments
- Monoclonal and Polyclonal Antibodies Research
- PI3K/AKT/mTOR signaling in cancer
Novo Nordisk (Denmark)
2008-2024
Novo Nordisk (United Kingdom)
2002-2023
Bangor University
2005
University of Copenhagen
2005
University of Sussex
2005
Steno Diabetes Centers
1998-2000
University of Toronto
1998
University of Warwick
1997
University of Birmingham
1995
Galectins are a family of lectins which share similar carbohydrate recognition domains (CRDs) and affinity for small β-galactosides, but show significant differences in binding specificity more complex glycoconjugates. We report here the x-ray crystal structure human galectin-3 CRD, with lactose N-acetyllactosamine, at 2.1-Å resolution. This represents first example CRD determined from galectin does not canonical 2-fold symmetric dimer organization. Comparison published structures...
Insulin regulates glucose homeostasis via binding and activation of the insulin receptor dimer at two distinct pairs sites 1 2. Here, we present cryo-EM studies full-length human (hIR) in an active state obtained non-saturating, physiologically relevant conditions. binds asymmetrically to under these conditions, occupying up three four possible sites. Deletion analysis together with site specific peptides analogs used show that both 2 are required for high affinity. We identify a homotypic...
The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes
Mammalian phospholipase D (PLD) activity becomes up-regulated when cells are stimulated by a variety of hormones, growth factors, and other extracellular signals. Two distinct PLDs, PLD1 PLD2, have been identified. The mechanism through which each PLD is activated, however, poorly understood. Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that activity, to lesser extent PLD2 in response epidermal factor (EGF). but not PLD1, associates with the...
The human UV-damaged DNA-binding protein Ddb1 associates with cullin 4 ubiquitin ligases implicated in nucleotide excision repair (NER). These complexes also contain the signalosome (CSN), but NER-relevant ubiquitination targets have not yet been identified. We report that fission yeast Ddb1, Cullin (Pcu4), and CSN subunits Csn1 Csn2 are required for degradation of ribonucleotide reductase (RNR) inhibitor Spd1. Ddb1-deficient cells >20-fold increased spontaneous mutation rate. This is...
This novel method enables specific measurement of the activation hybrid receptors formed between Insulin Receptor (IR) and Insulin-like Growth Factor 1 (IGF1R). These are present in tissues cell lines expressing both IR IGF1R. It is therefore challenging to separate homodimer receptor properties. ELISA enabled fast quantitative measurements activated receptors. The specificity obtained from a combination two antibodies for IGF1R an tyrosine phosphorylation site. was shown by...
Aims/Hypothesis There is controversy with respect to molecular characteristics of insulin analogues. We report a series experiments forming comprehensive characterisation the long acting analogues, glargine and detemir, in comparison human insulin, IGF-1, super-mitogenic X10. Methods measured binding ligands membrane-bound solubilised receptors, receptor activation mitogenicity number cell types. Results Detemir each displayed balanced affinity for (IR) isoforms A B. This was also true X10,...
Alanine scan of insulin receptor (IR)-B exon 11 and site-directed mutagenesis amino acid 718 in human IR-A IR-B were performed. Ligand affinities to wild type mutated receptors studied by displacement radioactive binding assay on secreted soluble midi or solubilized semi-purified full length stably expressed Baby Hamster Kidney cells. Phosphorylation IR response insulin, IGF1 IGF2 was measured using ELISA.Insulin, detemir glargine maximally showed two fold differences affinity for IR-B, but...
Insulin and insulin-like growth factor-1 stimulate specific responses in arteries, which may be disrupted by diet-induced obesity. We examined (1) temporal effects of high-fat diet compared to low-fat mice on insulin receptor, receptor/insulin-like receptor hybrid expression insulin/insulin-like factor-1-mediated Akt phosphorylation aorta; (2) vascular tone resistance arteries. Medium-term (5 weeks) decreased increased (~30%) only. After long-term (16 diet, was reduced ~30%, a further ~40%...
Phospholipase D (PLD)1 is quiescent in vitro and vivo until stimulated by classical protein kinase C (PKC) isoforms, ADP-ribosylation factor or Rho family members. By contrast, PLD2 has high basal activity, the mechanisms involved agonist-induced activation of are poorly understood. Using transiently transfected human embryonic kidney (HEK)-293 cells as a model system, we report present study that overexpressed HEK-293 exhibits regulatory properties similar to PLD1 when response insulin...
The insulin receptor (IR) belongs to the tyrosine kinase super family and plays an important role in glucose homeostasis. interacts with several large docking proteins that mediate signaling from receptor, including substrate (IRS) Src homology-2-containing (Src). Here, we applied bioluminescence resonance energy transfer 2 (BRET2) technique study IR pathways. interaction between substrates IRS1, IRS4 Shc was examined response ligands different properties. association interacting partners...
Translation across species of immunoassay results is often challenging due to the lack cross-species reactivity antibodies. In order investigate biology insulin and IGF1 receptors, we generated new versatile monoclonal assay antibodies using extracellular domain insulin/IGF1 hybrid receptor as bait protein in Adimab yeast antibody discovery platform antigen a rabbit platform. The resulting clones were screened for specificity well both tissue cell line derived samples. Using these...
Abstract Insulin analogue X10 has a higher mitogenic potency than native human insulin in vitro and supra-pharmacological doses of increased the incidence mammary tumours rats. Compared to insulin, binding affinity receptor IGF-1 receptor, but it is not known whether either or both characteristics are important for stimulation cell proliferation vivo . The aim this study was explore how contributes A mouse xenograft model established with rat L6 myoblast cells transfected (L6hIR cells)...
Phospholipase D (PLD)1 is quiescent in vitro and vivo until stimulated by classical protein kinase C (PKC) isoforms, ADP-ribosylation factor or Rho family members. By contrast, PLD2 has high basal activity, the mechanisms involved agonist-induced activation of are poorly understood. Using transiently transfected human embryonic kidney (HEK)-293 cells as a model system, we report present study that overexpressed HEK-293 exhibits regulatory properties similar to PLD1 when response insulin...
Insulin resistance impairs the cellular insulin response, and often precedes metabolic disorders, like type 2 diabetes, impacting an increasing number of people globally. Understanding molecular mechanisms in hepatic is essential for early preventive treatments. To elucidate changes signal transduction associated with hepatocellular resistance, we employed a multi-layered mass spectrometry-based proteomics approach focused on receptor (IR) signaling at interactome, phosphoproteome, proteome...
<title>Abstract</title> The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes. Insulin doses must be adjusted to ensure glucose values within normal range, but matching fluctuating levels is difficult since even a slightly higher dose than needed can lead hypoglycaemic incidence which anything from uncomfortable life-threatening. It has thus been long-standing goal engineer glucose-sensitive that auto-adjust its...
Abstract The potentially fatal cardiovascular effects of hypoglycaemia are not well understood and large animal models the counter-regulatory responses consequences insulin-induced needed to understand mechanisms in humans. aim this study was develop a human-like minipig model including healthy diabetic pigs investigate endocrine, electrocardiographic platelet effects. Hypoglycaemia induced using hyperinsulinaemic, hypoglycaemic clamp an insulin bolus protocol. Plasma glucose, glucagon,...
Conference Article| May 01 1997 Characterisation of a phospholipase Cδ from Schizosaccharomyces pombe RITA SLAABY; SLAABY 1Department Biological Sciences, University Warwick, Coventry CV4 7AL, UK. Tel: 01203 524204, Fax: 523701 E-mail: PDJT@dna.bio.warwick.ac.uk Search for other works by this author on: This Site PubMed Google Scholar TRACY KNOTT; KNOTT JOHN DAVEY Biochem Soc Trans (1997) 25 (2): 225S. https://doi.org/10.1042/bst025225s Views Icon Article contents Figures & tables Video...
Endothelial cells co-express insulin receptor (IR) and insulin-like growth factor-1 (IGF-1R) homodimers. Furthermore, association of αβ half receptors IGF-1 also occur resulting in insulin/IGF-1 hybrid receptors. An abundance has been associated with reduced sensitivity metabolic tissue. The aim this project is to study the differential expression vascular derived receptors, hybrids during resistance a diet-induced model obesity (DIO). C57BL/6 mice were fed on high-fat or low-fat diets ad...