A5027617773- Connexins and lens biology
- Ubiquitin and proteasome pathways
- Microtubule and mitosis dynamics
- Cellular transport and secretion
- Autophagy in Disease and Therapy
- Parkinson's Disease Mechanisms and Treatments
- Immunotherapy and Immune Responses
- Cellular Mechanics and Interactions
- Cell Adhesion Molecules Research
- Skin and Cellular Biology Research
- Protein Degradation and Inhibitors
- PI3K/AKT/mTOR signaling in cancer
- T-cell and B-cell Immunology
- Heat shock proteins research
- RNA Research and Splicing
- Trypanosoma species research and implications
- Protein Kinase Regulation and GTPase Signaling
- Mitochondrial Function and Pathology
- Pancreatic function and diabetes
- Pluripotent Stem Cells Research
- Lysosomal Storage Disorders Research
- Metabolism, Diabetes, and Cancer
- Endoplasmic Reticulum Stress and Disease
- 14-3-3 protein interactions
- Immune Response and Inflammation
University of Dundee
2016-2025
MRC Protein Phosphorylation and Ubiquitylation Unit
1993-2024
Advisory Board Company (United States)
2024
Medical Research Council
1993-2022
Institute of Medical Sciences
2021
University of Iceland
2021
Tokushima University
2021
AstraZeneca (United States)
2021
Wellcome Trust
1998-2009
University of Tsukuba
2009
Microbial products are sensed through Toll-like receptors (TLRs) and trigger a program of dendritic cell (DC) maturation that enables DCs to activate T cells. Although an accepted hallmark this response is eventual down-regulation DC endocytic capacity, we show TLR ligands first acutely stimulate antigen macropinocytosis, leading enhanced presentation on class I II major histocompatibility complex molecules. Simultaneously, actin-rich podosomes disappear, which suggests coordinated...
Mammalian AMP-activated protein kinase (AMPK) is the downstream component of a cascade that activated by cellular stresses associated with ATP depletion. AMPK exists as heterotrimeric αβγ complexes, where catalytic subunit has two isoforms (α1 and α2) different tissue distributions. The budding yeast homologue SNF1 complex, which essential for derepression glucose-repressed genes, seems to act direct phosphorylation transcription factors in nucleus. complexes containing α2 rather than α1...
Autophagic turnover of mitochondria, termed mitophagy, is proposed to be an essential quality-control (QC) mechanism pathophysiological relevance in mammals. However, if and how mitophagy proceeds within specific cellular subtypes vivo remains unclear, largely because a lack tractable tools models. To address this, we have developed "mito-QC," transgenic mouse with pH-sensitive fluorescent mitochondrial signal. This allows the assessment architecture vivo. Using confocal microscopy,...
LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients, but still little understood about how it regulated or functions. In the present study we have demonstrated that 14-3-3 isoforms interact with LRRK2. Consistent this, endogenous isolated from Swiss 3T3 cells various mouse tissues associated isoforms. We established binding mediated by phosphorylation at two conserved residues (Ser910 and Ser935) located before leucine-rich domain....
LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients. Since common mutation that replaces Gly2019 with serine residue enhances catalytic activity, small-molecule inhibitors might have utility treating disease. However, the effectiveness difficult to assess, as no physiological substrates or downstream effectors been identified could be exploited develop robust cell-based assay. We recently established bound 14-3-3 isoforms via its...
The Vps34 (vacuolar protein sorting 34) class III PI3K (phosphoinositide 3-kinase) phosphorylates PtdIns (phosphatidylinositol) at endosomal membranes to generate PtdIns(3)P that regulates membrane trafficking processes via its ability recruit a subset of proteins possessing PtdIns(3)P-binding PX (phox homology) and FYVE domains. In the present study, we describe highly selective potent inhibitor Vps34, termed VPS34-IN1, inhibits with 25 nM IC50 in vitro, but does not significantly inhibit...
Biofilms represent the predominant mode of microbial growth in natural environment. Bacillus subtilis is a ubiquitous Gram-positive soil bacterium that functions as an effective plant growth-promoting agent. The biofilm matrix composed exopolysaccharide and amyloid fiber-forming protein, TasA, assembles with aid small secreted BslA. Here we show natively synthesized BslA forms surface layers around biofilm. Biophysical analysis demonstrates can self-assemble at interfaces, forming elastic...
The polarization of macrophages into a regulatory-like phenotype and the production IL-10 plays an important role in resolution inflammation. We show this study that PGE2, combination with LPS, is able to promote anti-inflammatory characterized by high expression regulatory markers SPHK1 LIGHT via protein kinase A–dependent pathway. Both TLR agonists PGE2 phosphorylation transcription factor CREB on Ser133. However, although regulates transcription, mutation Ser133 Ala endogenous gene did...
Scientific Report26 June 2015Open Access Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation Agne Kazlauskaite MRC Protein Phosphorylation Ubiquitylation Unit, College of Life Sciences, University Dundee, UK Search more papers by this author R Julio Martínez-Torres Scott Wilkie Division Biological Chemistry Drug Discovery, Atul Kumar Julien Peltier Alba Gonzalez Clare Johnson Jinwei Zhang Anthony G Hope Mark Peggie Matthias...
Parkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of autophagy mitochondria, known as mitophagy. Here, we investigated role LRRK2, protein kinase frequently mutated PD, process vivo. Using mitophagy reporter mice, bearing either knockout LRRK2 or expressing pathogenic...
Mutations enhancing the kinase activity of leucine-rich repeat kinase-2 (LRRK2) cause Parkinson's disease (PD) and therapies that reduce LRRK2 are being tested in clinical trials. Numerous rare variants unknown significance have been reported, but how vast majority impact on function is unknown. Here, we investigate 100 linked to PD, including previously described pathogenic mutations. We identify 23 robustly stimulate activity, within N-terminal non-catalytic regions (ARM (E334K, A419V),...
HSP27 and alphaB-crystallin are both members of the small heat shock protein family. alphaB-crystalllin has been proposed to modulate intermediate filaments recently a mutation in identified as genetic basis desmin related myopathy. This disease is characterised its pathology by aggregates associated with alphaB-crystallin. Here we report that like glial fibrillary acidic vimentin filament networks unstressed U373MG astrocytoma cells. also keratin MCF7 cells, indicating this association not...
Abstract Dendritic cells expanded from mouse bone marrow (BMDC) with granulocyte/macrophage‐colony‐stimulating factor have potent T cell‐stimulatory properties both in vitro and vivo. This has been well documented for major histocompatibility complex (MHC) class II‐restricted responses, more recently using peptide‐loaded protein‐pulsed DC CD8 responses following adoptive transfer mice. An unresolved question concerns the capacity of BMDC to present exogenous antigen on MHC I molecules, an...
The transcription factor, forkhead in rhabdomyosarcoma (FKHR), is phosphorylated at three amino acid residues (Thr-24, Ser-256 and Ser-319) by protein kinase B (PKB)α. In the present study, mutagenesis has been used to study roles of these phosphorylation events regulating FKHR function transfected HEK-293 cells. We find that overexpression FKHR[S256A] (where → Ala) blocks PKB activity cells, preventing endogenous substrates FKHRL1 glycogen synthase kinase-3. Thus some reported effects this...
Recent studies indicate that the LKB1 is a key regulator of AMP-activated protein kinase (AMPK), which plays crucial role in protecting cardiac muscle from damage during ischemia. We have employed mice lack and skeletal studied how this affected activity AMPKalpha1/alpha2 under normoxic, ischemic, anoxic conditions. In heart lacking LKB1, basal AMPKalpha2 was vastly reduced not increased by ischemia or anoxia. Phosphorylation at site phosphorylation (Thr172) acetyl-CoA carboxylase-2,...
• The ability of Burkholderia phymatum STM815 to effectively nodulate Mimosa spp., and fix nitrogen ex planta, was compared with that the known symbiont Cupriavidus taiwanensis LMG19424. Both strains were equally effective symbionts M. pudica, but nodules formed by had greater nitrogenase activity. shown have a broader host range across genus than LMG19424, nodulating 30 out 31 species, 21 these effectively. LMG19424 nodulated only nine species. GFP-marked variants used visualise presence...