A5088586100- Skin and Cellular Biology Research
- Cellular Mechanics and Interactions
- Hippo pathway signaling and YAP/TAZ
- Polysaccharides and Plant Cell Walls
- Cell Adhesion Molecules Research
- Calpain Protease Function and Regulation
- Cell death mechanisms and regulation
- Plant Reproductive Biology
- Plant Surface Properties and Treatments
- interferon and immune responses
- Wnt/β-catenin signaling in development and cancer
- RNA regulation and disease
- Hair Growth and Disorders
- Galectins and Cancer Biology
- Autoimmune Bullous Skin Diseases
- Cancer Cells and Metastasis
- Glycosylation and Glycoproteins Research
- Advancements in Transdermal Drug Delivery
- Muscle Physiology and Disorders
- Nuclear Structure and Function
- Tissue Engineering and Regenerative Medicine
- Developmental Biology and Gene Regulation
- Genetics, Aging, and Longevity in Model Organisms
- Wound Healing and Treatments
- Pluripotent Stem Cells Research
University of Bath
2018-2024
Queen Mary University of London
2024
University of Vienna
2006-2020
Max Perutz Labs
2006-2020
Cell Therapy Catapult
2017-2019
King's College London
2013-2019
Guy's Hospital
2015-2019
Aarhus University
2001
Plectin is a major intermediate filament (IF)-based cytolinker protein that stabilizes cells and tissues mechanically, regulates actin dynamics, serves as scaffolding platform for signaling molecules. In this study, we show plectin deficiency cause of aberrant keratin cytoskeleton organization caused by lack orthogonal IF cross-linking. Keratin networks in plectin-deficient were more susceptible to osmotic shock-induced retraction from peripheral areas, their okadaic acid-induced disruption...
Integrin-based mechanotransduction involves a complex focal adhesion (FA)-associated machinery that is able to detect and respond forces exerted either through components of the extracellular matrix or intracellular contractile actomyosin network. Here, we show hitherto unrecognized regulatory role vimentin intermediate filaments (IFs) in this process. By studying fibroblasts which IFs were decoupled from FAs, because deficiency (V0) loss network anchorage due cytolinker protein plectin...
Abstract Individual human epidermal cells differ in their self-renewal ability. To uncover the molecular basis for this heterogeneity, we performed genome-wide pooled RNA interference screens and identified genes conferring a clonal growth advantage on normal neoplastic (cutaneous squamous cell carcinoma, cSCC) cells. The Hippo effector YAP was amongst top positive regulators both screens. By integrating network interactome with our data sets, identify WW-binding protein 2 (WBP2) as an...
Mutations in the cytoskeletal linker protein plectin result multisystemic diseases affecting skin and muscle with indications of additional vascular system involvement. To study mechanisms underlying disorders, we established plectin-deficient endothelial cell mouse models. We show that apart from perturbing vimentin cytoskeleton cells, deficiency leads to severe distortions adherens junctions (AJs) as well tight junctions, accompanied by an upregulation actin stress fibres increased...
Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition the two states, termed commitment, is poorly understood. Here, we characterise commitment by integrating transcriptomic proteomic data from disaggregated primary human keratinocytes held in suspension to induce Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 PPP3CA – promote differentiation negatively regulating ERK MAPK...
Autosomal recessive mutations in the cytolinker protein plectin account for multisystem disorders epidermolysis bullosa simplex (EBS) associated with muscular dystrophy (EBS-MD), pyloric atresia (EBS-PA), and congenital myasthenia (EBS-CMS). In contrast, a dominant missense mutation leads to disease EBS-Ogna, manifesting exclusively as skin fragility. We have exploited this trait study molecular basis of hemidesmosome failure EBS-Ogna reveal contribution homeostasis. generated knock-in mice...
In human skin the junction between epidermis and dermis undulates, width depth of undulations varying with age disease. When primary epidermal keratinocytes are seeded on collagen-coated polydimethylsiloxane (PDMS) elastomer substrates that mimic epidermal-dermal interface, stem cells become patterned by 24 h, resembling their organisation in living skin. We found cell density nuclear height were higher at base than tips PDMS features. Cells not only expressed levels marker β1 integrin but...
The transition of microtubules (MTs) from an assembled to a disassembled state plays essential role in several cellular functions. While MT dynamics are often linked those actin filaments, little is known about whether intermediate filaments (IFs) have influence on dynamics. We show here that plectin 1c (P1c), one the multiple isoforms IF-associated cytolinker protein plectin, acts as destabilizer. found MTs P1c-deficient (P1c(-/-)) keratinocytes more resistant toward nocodazole-induced...
The transmission of mechanical forces to the nucleus is important for intracellular positioning, mitosis and cell motility, yet contribution specific components cytoskeleton nuclear mechanotransduction remains unclear. In this study, we examine how crosstalk between cytolinker plectin F-actin controls keratin network organisation 3D morphology keratinocytes. Using micro-patterned surfaces precisely manipulate shape, find that adhesion spreading regulate size shape nucleus. Disruption through...
Plectin, a widespread intermediate filament-based cytolinker protein capable of interacting with variety cytoskeletal structures and plasma membrane-bound junctional complexes, serves essential functions in maintenance cell tissue cytoarchitecture. We have generated mouse line bearing floxed plectin alleles conditionally deleted stratified epithelia. This strategy enabled us to study the consequences deficiency this particular type tissues context whole organism without loss affecting other...
Plectin is the prototype of an intermediate filament (IF)-based cytolinker protein. It affects cells mechanically by interlinking and anchoring cytoskeletal filaments acts as scaffolding docking platform for signaling proteins to control cytoskeleton dynamics. The most common disease caused mutations in human plectin gene, epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), characterized severe skin blistering progressive dystrophy. Therefore, we compared biomechanical properties...
The detachment of epithelial cells from the basal matrix during wound healing and differentiation keratinocytes requires disassembly hemidesmosomal multiprotein adhesion complex. Integrin α6β4-plectin interaction plays a major role in formation hemidesmosomes, thus mechanisms regulating this should be critical also for process. Here we show that particular plectin isoform (1a) interacts with Ca2+-sensing protein calmodulin Ca2+-dependent manner. As result interaction, binding...
Human epidermal stem cells initiate terminal differentiation when spreading is restricted on ECM-coated micropatterned islands, soft hydrogels or hydrogel-nanoparticle composites with high nanoparticle spacing. The effect of substrate topography, however, incompletely understood. To explore this, primary human keratinocytes enriched for were seeded a topographical library over 2000 different topographies in the micrometre range. Twenty-four hours later proportion expressing marker...
Previous studies have unmasked plectin, a uniquely versatile intermediate filament-associated cytolinker protein, to be essential for skin and skeletal muscle integrity. Different sets of isoforms the protein were found stabilize cells mechanically, regulate cytoskeletal dynamics, serve as scaffolding platform signaling molecules. Here, we investigated whether similar scenario prevails in myelinating Schwann cells. Using isoform-specific antibodies, two plectin variants predominantly...
Abstract Epidermal homeostasis depends on a balance between self-renewal of stem cells and terminal differentiation their progeny. Notch signalling is known to play role in epidermal cell patterning differentiation. However, the molecular mechanisms are incompletely understood. Here we demonstrate dynamic patterns ligand receptor expression cultured human epidermis. Notch2 3 act together promote differentiation, while Notch1 decreases proliferation. The Jagged1 triggers when presented an...
Plectin, a universally expressed multi-functional cytolinker protein, is crucial for intermediate filament networking, including crosstalk with actomyosin and microtubules. In addition to its involvement in number of diseases affecting skin, skeletal muscle, heart, other stress-exposed tissues, indications neuropathological role plectin have emerged. Having identified P1c as the major isoform neural tissues previous studies, our aim present work was investigate whether, by which...
Abstract On the basis of enhanced tumor accumulation and bone affinity, gallium compounds are under development as anticancer antimetastatic agents. In this study, we analyzed molecular targets one lead complexes [KP46, Tris(8-quinolinolato)gallium(III)] focusing on colon lung cancer. Within a few hours, KP46 treatment at low micromolar concentrations induced cell body contraction loss adhesion followed by prompt decomposition. This rapid KP46-induced death lacked classic apoptotic features...