A5054181982- Protein Kinase Regulation and GTPase Signaling
- PI3K/AKT/mTOR signaling in cancer
- Cellular transport and secretion
- Parkinson's Disease Mechanisms and Treatments
- Metabolism, Diabetes, and Cancer
- Ubiquitin and proteasome pathways
- Ion Transport and Channel Regulation
- Pancreatic function and diabetes
- Lysosomal Storage Disorders Research
- Microtubule and mitosis dynamics
- Melanoma and MAPK Pathways
- Cancer-related Molecular Pathways
- Biotin and Related Studies
- Ion channel regulation and function
- Fungal and yeast genetics research
- Protein Degradation and Inhibitors
- Genetic factors in colorectal cancer
- Chronic Lymphocytic Leukemia Research
- Protein Tyrosine Phosphatases
- Retinal Development and Disorders
- Hippo pathway signaling and YAP/TAZ
- DNA Repair Mechanisms
- Plant Gene Expression Analysis
- Neurological diseases and metabolism
- Cancer, Hypoxia, and Metabolism
MRC Protein Phosphorylation and Ubiquitylation Unit
2016-2025
University of Dundee
2016-2025
Medical Research Council
2016-2025
Research Network (United States)
2021-2025
University of Padua
2024-2025
Babcock University
2024
Benue State University
2024
University of Ilorin
2024
Ninewells Hospital
1996-2024
Aligning Science Across Parkinson's
2022
PD 098059 has been shown previously to inhibit the dephosphorylated form of mitogen-activated protein kinase kinase-1 (MAPKK1) and a mutant MAPKK1(S217E,S221E), which low levels constitutive activity (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. Saltiel, R.(1995) Proc. Natl. Acad. Sci. U. 92, 7686-7689). Here we report that does not Raf-activated MAPKK1 but it prevents activation by Raf or MEK in vitro at concentrations (IC50 = 2-7 μM) similar those MAPKK1(S217E,S221E). inhibited...
The specificities of 65 compounds reported to be relatively specific inhibitors protein kinases have been profiled against a panel 70–80 kinases. On the basis this information, effects that we studied in cells and other data literature, recommend use following small-molecule inhibitors: SB 203580/SB202190 BIRB 0796 used parallel assess physiological roles p38 MAPK (mitogen-activated kinase) isoforms, PI-103 wortmannin inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 with...
Voluntary surveillance systems are subject to under-reporting.Figures may underestimate true numbers.Miscategorisation of probable country infection by presuming the with highest prevalence as likely will number infections acquired in United Kingdom, particularly among people originating from countries high prevalence.New HIV diagnoses do not represent new infections, diagnosis can occur at any point between and death, which natural course is typically 10-12 years.Furthermore, reports...
The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy charge that acts as 'metabolic master switch' and inhibits cell proliferation. Activation requires phosphorylation Thr172 AMPK within the activation loop by upstream kinases (AMPKKs) have not been identified. Recently, we identified three related acting yeast homolog AMPK. Although they do obvious mammalian homologs, are to LKB1, tumor suppressor mutated in human Peutz-Jeghers cancer syndrome. We recently showed...
Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that have been implicated in the regulation of cell growth, proliferation, survival, differentiation and cytoskeletal changes. One best characterized targets PI3K lipid products is protein kinase Akt or B (PKB). In quiescent cells, PKB resides cytosol a low-activity conformation. Upon cellular stimulation, activated through recruitment to membranes by phosphorylation 3ʹ-phosphoinositide-dependent kinase-1 (PDK1). Here we...
Phosphorylation sites in members of the protein kinase A (PKA), PKG, and PKC subfamily are conserved. Thus, PKB PDK1 may be responsible for phosphorylation isotypes. phosphorylated activation loop PKCζ PKCδ vitro a phosphoinositide 3-kinase (PI 3-kinase)–dependent manner vivo human embryonic kidney (293) cells. All family tested formed complexes with PDK1. PDK1-dependent was stimulated by combined activators. The response to serum stimulation cells PI 3-kinase–dependent enhanced coexpression.
We have investigated the role of subcellular localization in regulation protein kinase B (PKB) activation. The myristoylation/palmitylation motif from Lck tyrosine was attached to N terminus alter its location. Myristoylated/palmitylated (m/p)-PKBα associated with plasma membrane transfected cells, whereas wild-type mostly cytosolic. activity m/p-PKBα 60-fold higher compared unstimulated enzyme, and could not be stimulated further by growth factors or phosphatase inhibitors.In vivo 32P...
OBJECTIVE The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase (AMPK). Activation AMPK can suppress tumor formation and inhibit cell growth in addition lowering blood glucose levels. We tested hypothesis that reduces risk cancer people with type 2 diabetes. RESEARCH DESIGN AND METHODS In an observational cohort study using record-linkage databases based Tayside, Scotland, U.K., we identified diabetes who were new users...
Growth factor induced activation of phosphoinositide 3-kinase and protein kinase B (PKB) leads to increased activity the mammalian target rapamycin (mTOR). This subsequently phosphorylation eIF4E binding protein-1 (4EBP1) p70 ribosomal S6 (p70(S6K)), both which are important steps in stimulation translation. The translation is attenuated cells deprived amino acids this associated with attenuation 4EBP1 p70(S6K) activation. It has been suggested that PKB regulates mTOR function by although...
Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise predominant genetic cause of Parkinson's disease (PD). G2019S, most common amino acid substitution activates two- to threefold. This has motivated development LRRK2 inhibitors; however, poor consensus on physiological substrates hampered clinical such therapeutics. We employ a combination phosphoproteomics, genetics, and pharmacology unambiguously identify subset Rab GTPases as key...
SGK1 (serum- and glucocorticoid-induced protein kinase 1) is a member of the AGC (protein A/protein G/protein C) family kinases activated by agonists including growth factors. regulates diverse effects extracellular phosphorylating regulatory proteins that control cellular processes such as ion transport growth. Like other kinases, activation triggered phosphorylation threonine residue within T-loop domain serine lying C-terminal hydrophobic motif (Ser(422) in SGK1). PDK1...
Missense mutations in PTEN-induced kinase 1 (PINK1) cause autosomal-recessive inherited Parkinson's disease (PD). We have exploited our recent discovery that recombinant insect PINK1 is catalytically active to test whether directly phosphorylates 15 proteins encoded by PD-associated genes as well reported bind PINK1. discovered efficiently only one of these proteins, namely the E3 ligase Parkin. mapped phosphorylation site a highly conserved residue within Ubl domain Parkin at Ser(65). show...
We have previously reported that the Parkinson's disease-associated kinase PINK1 (PTEN-induced putative 1) is activated by mitochondrial depolarization and stimulates Parkin E3 ligase phosphorylating Ser65 within its Ubl (ubiquitin-like) domain. Using phosphoproteomic analysis, we identified a novel ubiquitin phosphopeptide phosphorylated at was enriched 14-fold in HEK (human embryonic kidney)-293 cells overexpressing wild-type stimulated with uncoupling agent CCCP (carbonyl cyanide...
The substrate specificity of protein kinase‐Bα (PKBα, also known as RAC kinase or Akt) was investigated using synthetic peptide substrates related to the sequence surrounding phosphorylation site on glycogen synthase kinase‐3 (GSK3). minimum motif required for efficient Arg‐Xaa‐Arg‐Yaa‐Zaa‐Ser/Thr‐Hyd, where Xaa is any amino acid, Yaa and Zaa are small residues other than glycine Hyd a bulky hydrophobic residue (Phe, Leu). most effective substrate, Arg‐Pro‐Arg‐Thr‐Ser‐Ser‐Phe, phosphorylated...