A5028520716- Neuroscience and Neuropharmacology Research
- Cellular transport and secretion
- Ion channel regulation and function
- Cellular Mechanics and Interactions
- Nerve injury and regeneration
- Genetic factors in colorectal cancer
- Genetics and Neurodevelopmental Disorders
- Melanoma and MAPK Pathways
- Protein Kinase Regulation and GTPase Signaling
- Receptor Mechanisms and Signaling
- Axon Guidance and Neuronal Signaling
- Neurogenesis and neuroplasticity mechanisms
- Spatial and Panel Data Analysis
- Hippo pathway signaling and YAP/TAZ
- Virology and Viral Diseases
- Regional Economics and Spatial Analysis
- Nuclear Receptors and Signaling
- Cytokine Signaling Pathways and Interactions
- RNA Research and Splicing
- Retinal Development and Disorders
- Colorectal Cancer Treatments and Studies
- Heat shock proteins research
- Chromatin Remodeling and Cancer
- Endoplasmic Reticulum Stress and Disease
- Sirtuins and Resveratrol in Medicine
Temple University
2015-2025
Temple University Hospital
2013-2024
Morriston Hospital
2016-2021
Bronllys Hospital
2021
Noah's Ark Children's Hospital for Wales
2019
Shriners Hospitals for Children
2013-2017
Wellcome Centre for Mitochondrial Research
2016
Evelina London Children's Healthcare
2016
St Thomas' Hospital
2016
Swansea Bay University Health Board
2016
The Axin‐dependent phosphorylation of β‐catenin catalysed by glycogen synthase kinase‐3 (GSK3) is inhibited during embryogenesis. This protects against ubiquitin‐dependent proteolysis, leading to its accumulation in the nucleus, where it controls expression genes important for development. Frequently rearranged advanced T‐cell lymphomas 1 (FRAT1) a mammalian homologue GSK3‐binding protein (GBP), which appears play key role correct establishment dorsal‐ventral axis Xenopus laevis . Here, we...
Significance Dual leucine-zipper kinase (DLK) is essential for responses to nerve injury and subsequent neural regeneration by controlling transfer of signals from damaged distal axons neuronal cell bodies. However, DLK predicted be freely diffusible, raising the question how it conveys long-distance, directional signals. Here we report that direct modification with lipid palmitate, a process called palmitoylation, critical retrograde signaling. At molecular level, palmitoylation targets...
Glutamate receptor interacting protein 1 (GRIP1) is a neuronal scaffolding that interacts directly with the C termini of glutamate receptors 2/3 (GluA2/3) via its PDZ domains 4 to 6 (PDZ4–6). We found an association ( P < 0.05) SNP within PDZ4-6 genomic region autism by genotyping autistic patients n = 480) and matched controls 480). Parallel sequencing identified five rare missense variants or near PDZ4–6 only in cohort, resulting higher cumulative mutation load 0.032). Two correlated...
Dual leucine-zipper kinase (DLK; a MAP3K) mediates neuronal responses to diverse injuries and insults through the c-Jun N-terminal (JNK) family of mitogen-activated protein kinases (MAPKs). Here, we identified two ways which DLK is coupled neural-specific isoform JNK3 control prodegenerative signaling. catalyzed positive feedback phosphorylation that further activated locked DLK-JNK3 module in highly active state. Neither homologous MAP3Ks nor MAPK could support this loop. Unlike related...
Abstract Dual leucine-zipper kinase (DLK) drives acute and chronic forms of neurodegeneration, suggesting that inhibiting DLK signaling could ameliorate diverse neuropathological conditions. However, direct inhibition DLK’s domain in human patients conditional knockout mice both cause unintended side effects, including elevated plasma neurofilament levels, indicative neuronal cytoskeletal disruption. Indeed, we found a inhibitor acutely disrupted the axonal cytoskeleton caused vesicle...
SAPK3 (stress-activated protein kinase-3, also known as p38γ) is a member of the mitogen-activated kinase family; it phosphorylates substrates in response to cellular stress, and has been shown bind through its C-terminal sequence PDZ domain α1-syntrophin. In present study, we show that SAP90 [(synapse-associated 90; PSD-95 (postsynaptic density-95)] novel physiological substrate for both SAPK3/p38γ ERK (extracellular-signal-regulated kinase). binds preferentially third residues Thr287...
PSD-95/SAP90/DLG/ZO-1 (PDZ) domain-mediated protein–protein interactions play important roles in regulating AMPA receptor trafficking and neuronal plasticity. GRIP1 GRIP2 are homologous multi-PDZ domain-containing proteins that bind to the C-termini of AMPA-R GluA2 GluA3 subunits. Previous attempts determine cellular neurons have been complicated by nonspecific reagents, embryonic lethality conventional KO mice. To circumvent these issues we developed a conditional targeted deletion strategy...
The palmitoyl acyltransferase (PAT) DHHC8 is implicated in synaptic regulation but few substrates are known. Here we report that binds and palmitoylates the PDZ domain-containing protein PICK1 at a cysteine residue essential for long-term depression (LTD) cultured mouse cerebellar Purkinje neurons. Cerebellar LTD palmitoylation-dependent induction of requires DHHC8. Furthermore, critical substrate whose palmitoylation necessary LTD. These results identify first required specific form...
AMPA receptors (AMPARs) are the major excitatory of brain and fundamental to synaptic plasticity, memory, cognition. Dynamic recycling AMPARs in neurons is regulated through several types posttranslational modification, including phosphorylation. Here, we identify a previously unidentified signal transduction cascade that modulates phosphorylation serine residue 863 (S863) GluA1 AMPAR subunit controls surface trafficking neurons. Activation EphR-Ephrin pathway enhances S863 Further, EphB2...
Precise regulation of the dendritic spine actin cytoskeleton is critical for neurodevelopment and neuronal plasticity, but how neurons spatially control dynamics not well defined. Here, we identify direct palmitoylation regulator LIM kinase-1 (LIMK1) as a novel mechanism to spine-specific dynamics. A conserved palmitoyl-motif necessary sufficient target LIMK1 spines anchor in spines. ShRNA knockdown/rescue experiments reveal that essential normal polymerization, structural plasticity...
Extracellular signal-regulated kinase (ERK) signaling is important for neuronal synaptic plasticity. We report here that the protein ribosomal S6 (RSK)2, a downstream target of ERK, uses C-terminal motif to bind several PDZ domain proteins in heterologous systems and vivo . Different RSK isoforms display distinct specificities their interactions with proteins. Mutation RSK2 ligand does not inhibit activation intact cells or phosphorylation peptide substrates by vitro but greatly reduces...
A MAP kinase homologue, termed the reactivating (RK), lies in a signalling pathway which mediates cellular responses to stress. Here we demonstrate that stress‐induced activation of RK human KB cells is accompanied by phosphorylation Thr‐180 and Tyr‐182, both residues required for this enzyme.
Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis a panel of testicular germ cell tumours search for novel and identified frequent small deletion on 6q25.3 just one gene, ZDHHC14. The expression ZDHHC14, putative protein palmitoyltransferase with unknown cellular function, was decreased at both RNA levels in tumours. ZDHHC14 also significantly prostate cancer samples lines. In addition our findings genetic clinical samples, inducible...
The mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) controls growth and proliferation non-neuronal cells, while during neuronal development mTORC1 responds to glutamate neurotrophins promote migration dendritic arborization. Recent studies reveal that signaling complexes are assembled on lysosomal membranes, but how membrane targeting is regulated not fully clear. Our examination palmitoyl-proteomic databases additional bioinformatic analyses revealed several proteins predicted...
The palmitoyl acyltransferase (PAT) ZDHHC14 is highly expressed in the hippocampus and only PAT predicted to bind Type-I PDZ domain-containing proteins. However, ZDHHC14’s neuronal roles are unknown. Here, we identify Membrane-associated Guanylate Kinase (MaGUK) PSD93 as a direct interactor substrate. PSD93, but not other MaGUKs, localizes axon initial segment (AIS). Using lentiviral-mediated shRNA knockdown rat hippocampal neurons, find that controls palmitoylation AIS clustering of also...
After optic nerve crush (ONC), the cell bodies and distal axons of most retinal ganglion cells (RGCs) degenerate. RGC somal axon degenerations were previously thought to be controlled by two parallel pathways, involving activation kinase dual leucine-zipper (DLK) loss survival factor nicotinamide mononucleotide adenylyltransferase-2 (NMNAT2), respectively. Here, we report that palmitoylation both DLK NMNAT2 palmitoyl acyltransferase ZDHHC17 couples these signals. ZDHHC17-dependent enables...
Abstract Atr is a serine/threonine kinase, known to sense single-stranded DNA breaks and activate the damage checkpoint by phosphorylating Chek1, which inhibits Cdc25, causing cell cycle arrest. This pathway has not been implicated in neuroregeneration. We show that Drosophila sensory neurons removing or overexpressing Cdc25 promotes regeneration, whereas Chek1 overexpression, knockdown impedes regeneration. Inhibiting Atr-associated complex regeneration improves synapse/behavioral recovery...