A5016819318- Metabolism, Diabetes, and Cancer
- Pancreatic function and diabetes
- Wnt/β-catenin signaling in development and cancer
- Protein Kinase Regulation and GTPase Signaling
- Adipose Tissue and Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Axon Guidance and Neuronal Signaling
- Alzheimer's disease research and treatments
- Ubiquitin and proteasome pathways
- Diet and metabolism studies
- Cancer-related gene regulation
- Microtubule and mitosis dynamics
- Genomics, phytochemicals, and oxidative stress
- Cancer Treatment and Pharmacology
- Regulation of Appetite and Obesity
- FOXO transcription factor regulation
- Diabetes Management and Research
- Hippo pathway signaling and YAP/TAZ
- Endoplasmic Reticulum Stress and Disease
- Cancer Research and Treatments
- Nerve injury and regeneration
- Cancer-related Molecular Pathways
- Cellular transport and secretion
- Glutathione Transferases and Polymorphisms
- Cancer, Hypoxia, and Metabolism
University of Dundee
2016-2025
Ninewells Hospital
2013-2024
Stracathro Hospital
2015
Texas Biomedical Research Institute
2011
Neurosciences Institute
2010
Vanderbilt University
1995-2007
MRC Protein Phosphorylation and Ubiquitylation Unit
1992-1994
University of Calgary
1989-1992
Western University
1985
Cornell University
1966
The beta-isoform of glycogen synthase kinase-3 (GSK3 beta) isolated from rabbit skeletal muscle was inactivated 90-95% following incubation with MgATP and either MAP kinase-activated protein kinase-1 (MAPKAP kinase-1, also termed RSK-2) or p70 S6 kinase (p70S6K), re-activated phosphatase 2A. MAPKAP p70S6K phosphorylated the same tryptic peptide on GSK3 beta, site phosphorylation identified as serine located nine residues N-terminus protein. inhibitory effect Ser-9 beta activity observed...
Recently, loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, have been identified as cause of common skin condition ichthyosis vulgaris (which is characterised by dry, scaly skin). These mutations, which are carried up to 10% people, also represent a strong genetic predisposing factor for atopic eczema, asthma allergies. Profilaggrin major component keratohyalin granules within epidermal granular cells. During terminal differentiation, approximately 400...
Identification of regulatable mechanisms by which transcription factor NF-E2 p45-related 2 (Nrf2) is repressed will allow strategies to be designed that counter drug resistance associated with its upregulation in tumours harbour somatic mutations Kelch-like ECH-associated protein-1 (Keap1), a gene encodes joint adaptor and substrate receptor for the Cul3-Rbx1/Roc1 ubiquitin ligase. We now show mouse Nrf2 contains two binding sites β-transducin repeat-containing protein (β-TrCP), acts as...
Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles brains patients with Alzheimer's disease (AD) and related tauopathies is a crucial factor pathogenesis these disorders. Though diverse kinases have been implicated phosphorylation, protein phosphatase 2A (PP2A) seems to be major phosphatase. Using murine primary neurons from wild-type human transgenic mice, we show that antidiabetic drug metformin induces PP2A activity reduces phosphorylation at...
Nearly 100 proteins are proposed to be substrates for GSK3, suggesting that this enzyme is a fundamental regulator of almost every process in the cell, tissue body. However, it not certain how many these regulated by GSK3 vivo. Clearly, identification physiological functions will greatly aided its bona fide substrates, and development as therapeutic target highly influenced range actions, hence need accurately establish true cells. In paper evidence likely targets assessed, highlighting key...
Insulin regulates the rate of expression many hepatic genes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). The these genes is also abnormally regulated in type 2 diabetes. We demonstrate here that treatment hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent activates AMP-activated protein kinase (AMPK), mimics ability insulin to repress PEPCK gene transcription. It partially represses G6Pase transcription yet has...
Elevated glycogen synthase kinase-3 (GSK-3) activity is associated with Alzheimer disease. We have found that collapsin response mediator proteins (CRMP) 2 and 4 are physiological substrates of GSK-3. The amino acids targeted by GSK-3 comprise a hyperphosphorylated epitope first identified in plaques isolated from brain. Expression wild type CRMP2 primary hippocampal neurons or SH-SY5Y neuroblastoma cells promotes axon elongation. However, GSK-3-insensitive mutant has dramatically reduced...
The α‐isoform of glycogen synthase kinase‐3 (GSK3α) was inactivated by 80% towards a synthetic peptide substrate upon incubation with Mg‐ATP and either MAP kinase‐activated protein (MAPKAP) kinase‐1 or p70 S6 kinase. Inactivation kinase resulted from the phosphorylation Ser‐21 reversed treatment phosphatase 2A 1 . Phosphorylation also decreased GSK3α activity synthase, inhibitor‐2 c‐jun. specificity GSK3a similar to GSK3β, but heparin stimulated dephosphorylated form (6‐fold) more than...
A major action of insulin is to regulate the transcription rate specific genes. The expression these genes dramatically altered in type 2 diabetes. For example, two hepatic genes, glucose-6-phosphatase and PEPCK, normally inhibited by insulin, but diabetes, their insensitive insulin. An agent that mimics effect on would reduce gluconeogenesis glucose output, even presence resistance. repressive actions are dependent phosphatidylinositol (PI) 3-kinase. However, molecules lie between this...
Collapsin response mediator proteins (CRMPs) are a family of neuron-enriched that regulate neurite outgrowth and growth cone dynamics. Here, we show Cdk5 phosphorylates CRMP1, CRMP2, CRMP4, priming for subsequent phosphorylation by GSK3 in vitro. In contrast, DYRK2 primes CRMP4 only. The inhibitor purvalanol decreases the CRMP neurons, whereas CRMP1 but not is decreased Cdk5(-/-) cortices. Stimulation neuroblastoma cells with IGF1 or TPA activity concomitantly CRMP2 phosphorylation....
Mitogen‐activated protein‐kinase (MAP) kinase‐activated protein kinases 1 and 2 (MAPKAP kinase‐1, MAPKAP kinase‐2), were found to phosphorylate bacterially expressed human tyrosine hydroxylase in vitro at comparable rates other proteins thought be physiological substrates of these kinases. The phosphorylation all four alternatively spliced forms by kinases‐1 ‐2 reached plateau values mol/mol subunit subunit, respectively; the sites identified as Ser40 kinase‐1) Ser19 kinase‐2). In contrast...
Abstract Collapsin response mediator protein 2 (CRMP2) is an abundant brain‐enriched that can regulate microtubule assembly in neurons. This function of CRMP2 regulated by phosphorylation glycogen synthase kinase 3 (GSK3) and cyclin‐dependent 5 (Cdk5). Here, using novel phosphospecific antibodies, we demonstrate at Ser522 (Cdk5‐mediated) increased Alzheimer’s disease (AD) brain, while expression the closely related isoform CRMP4 are not altered. In addition, Cdk5 GSK3 sites cortex...
LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein (AMPK) 12 other closely related kinases. Liver-specific ablation of causes increased glucose production in hepatocytes vitro hyperglycaemia fasting mice vivo. Here we report the salt-inducible kinases (SIK1, 2 3), members AMPK-related family, play key role as gluconeogenic suppressors downstream liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation transcriptional...
J. Neurochem. (2010) 115 , 974–983. Abstract Mammalian glycogen synthase kinase‐3 (GSK3) is generated from two genes, GSK3α and GSK3β, while a splice variant of GSK3β (GSK3β2), containing 13 amino acid insert, enriched in neurons. deletions generate distinct phenotypes. Here, we show that phosphorylation CRMP2, CRMP4, β‐catenin, c‐Myc c‐ Jun some residues on tau associated with Alzheimer’s disease, altered cortical tissue lacking both isoforms GSK3. This confirms they are physiological...
Abstract Background Leptin and insulin are long-term regulators of body weight. They act in hypothalamic centres to modulate the function specific neuronal subtypes, by altering transcriptional control releasable peptides modifying electrical activity. A key cellular signalling intermediate, implicated food intake these hormones, is enzyme phosphoinositide 3-kinase. In this study we have explored further linkage between other mediators leptin action on rat arcuate nucleus neurones mouse cell...
Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step in hepatic gluconeogenesis. Glucagon (via second messenger cAMP) and glucocorticoids stimulate transcription of PEPCK gene, whereas insulin phorbol esters inhibit, a dominant fashion, these effects. Wortmannin, an inhibitor phosphatidylinositol 3-kinase, prevents stimulation glycogen synthesis, glucose transport, mitogen-activated protein kinase, p70/p85 ribosomal S6 kinase by insulin. We now show that wortmannin can...
An improved procedure has been developed for the isolation of insulin‐stimulated protein kinase‐1 (ISPK‐1), an S6 kinase‐II homologue, by which 0.5 mg highly purified enzyme can be obtained within four days. The sequences tryptic peptides from ISPK‐1 (100 residues) revealed 100% identity with predicted product rsk mo ‐2, a cDNA clone isolated mouse F2 cell line library [Alcorta, D. A., Crews, C. M., Sweet, L. J., Bankston, L., Jones, S. W. and Erikson, R. (1989) Mol. Cell. Biol. 9 ,...
Caldesmon is known to bind smooth muscle myosin.Ca2*/calmodulin-dependent phosphorylation of caldesmon completely blocks its interaction with myosin.Cleavage at 2 cysteine residues by 2-nitro-5-thiocyanobenzoic acid (NTCB) occurs initially one site yield 108-kDa and 21.2-kDa peptides subsequently the second within peptide 85-kDa 23.5-kDa fragments.The retains ability myosin.The N-terminal (95 kDa) C-terminal (42 chymotryptic were isolated digested NTCB: actinand calmodulin-binding was not...