Biomedical subjects

Gareth E Jones

Publications and source records attributed to Gareth E Jones.

28 records · Page 2Linked to original sources

PubMed2003

Requirement for PI 3-kinase gamma in macrophage migration to MCP-1 and CSF-1.

Phosphoinositide 3-kinases (PI3Ks) are important regulators of cell migration. The PI3K isoform gamma is primarily expressed in haematopoietic cells, and is activated by G protein-coupled receptors (GPCRs). Here, we investigate the contribution of PI3Kgamma to macrophage responses to chemoattractants, using bone marrow-derived macrophages from wild-type and PI3Kgamma-null mice. We observe that early membrane ruffling induced by MCP-1, which activates a GPCR, or by CSF-1, which activates a tyrosine kinase receptor, is unaltered in PI3Kgamma(-/-) mice, although by 30 min MCP-1-induced cell polarization was strongly reduced in PI3Kgamma(-/-) compared to wild-type macrophages. The migration behaviour of the macrophages was analysed by time-lapse microscopy in Dunn chemotaxis chambers. PI3Kgamma(-/-) macrophages showed reduced migration speed and translocation, and no chemotaxis to MCP-1. Interestingly, there was also a reduction in migration efficiency in PI3Kgamma(-/-) macrophages stimulated with CSF-1 although early CSF-1R signalling was normal. These results indicate that the initial actin reorganization induced by either a GPCR or tyrosine kinase receptor agonist is not dependent on PI3Kgamma, whereas PI3Kgamma is needed for optimal migration of macrophages to either agonist.

Actin Cytoskeleton↗

PubMed2003

GPI-anchored uPAR requires Endo180 for rapid directional sensing during chemotaxis.

Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in cell guidance and chemotaxis during normal and pathological events. uPAR is GPI-anchored and the mechanism by which it transmits intracellular polarity cues across the plasma membrane during directional sensing has not been elucidated. The constitutively recycling endocytic receptor Endo180 forms a trimolecular complex with uPAR in the presence of uPA, hence its alternate name uPAR-associated protein. Here, we demonstrate that Endo180 is a general promoter of random cell migration and has a more specific function in cell chemotaxis up a uPA gradient. Endo180 expression was demonstrated to enhance uPA-mediated filopodia production and promote rapid activation of Cdc42 and Rac. Expression of a noninternalizing Endo180 mutant revealed that promotion of random cell migration requires receptor endocytosis, whereas the chemotactic response to uPA does not. From these studies, we conclude that Endo180 is a crucial link between uPA-uPAR and setting of the internal cellular compass.

Animals↗

PubMed2003

Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110delta.

Class IA phosphoinositide 3'-kinases (PI3Ks) regulate many cellular processes downstream of tyrosine kinases and Ras. Despite a clear implication of PI3K in cancer, little is known about the distribution of the different PI3K isoforms in malignant cells. We screened a large panel of tissues and cell lines for expression of class IA PI3Ks, and document a ubiquitous expression of the p110alpha and p110beta isoforms but a variable and more restricted tissue distribution of the p110delta isoform. Originally found in WBCs, p110delta was also detected in some nonhematopoietic cell types especially those of breast or melanocytic origin, both in the untransformed and transformed state. Isoform-specific neutralization of PI3K isoforms in breast cancer cell lines (by PI3K antibody microinjection or a p110delta-selective pharmacological inhibitor) demonstrated that p110delta is the most important class IA PI3K in the regulation of epidermal growth factor-driven motility in vitro, controlling the directionality and, to a lesser extent, the speed of migration. In contrast, p110beta was required for the direction but not the speed of migration, whereas p110alpha did not impact on either of these parameters. These results show a nonredundant function of PI3K isoforms downstream of the epidermal growth factor receptor and indicate that the presence of p110delta may confer breast cancer cells with selective migratory capacities. The potential clinical implications of p110delta expression in non-WBC-derived tumors are discussed.

Animals↗

PubMed2003

Polarised migration: cofilin holds the front.

Persistent cell locomotion is a key feature of eukaryotic cells responding to diverse physiological cues. New work now directly implicates ADF/cofilin proteins as essential regulators of polarised cell migration.

Actin Depolymerizing Factors↗

PubMed2002

N-WASP activation by a beta1-integrin-dependent mechanism supports PI3K-independent chemotaxis stimulated by urokinase-type plasminogen activator.

Urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR) and epidermal growth factor (EGF)-EGF receptor (EGFR) expression is highly correlated with breast cancer metastasis. Phosphoinositide 3-kinase (PI3K), small Rho GTPases, such as Cdc42 and Rac1, and neuronal Wiskott Aldrich syndrome protein (N-WASP) are key effectors that regulate dynamic changes in the actin cytoskeleton and cell migration. uPA- and EGF-stimulated chemotaxis, cytoskeletal rearrangements and activation of Cdc42, Rac1 and N-WASP were studied in the highly metastatic human breast cancer cell line MDA MB 231. These studies reveal that divergent signalling occurs downstream of PI3K. The activity of PI3K was not necessary for uPA-induced chemotactic responses, but those induced by EGF were entirely dependent upon PI3K. Furthermore, PI3K-independent chemotactic signalling by uPA was shown to involve disruption of an interaction between beta(1)-integrins and N-WASP and translocation of N-WASP to the actin cytoskeleton.

Actins↗

PubMed2002

The effect of galectin-1 on the differentiation of fibroblasts and myoblasts in vitro.

Normal murine dermal fibroblasts implanted into the muscles of the mdx mouse, a model for Duchenne muscular dystrophy, not only participate in new myofibre formation but also direct the expression of the protein dystrophin which is deficient in these mice. We have reported that the lectin galectin-1 is implicated in the conversion of dermal fibroblasts to muscle. In the current work we confirm the presence of galectin-1 in the medium used for conversion. Furthermore we report that exposure of clones of dermal fibroblasts to this lectin results in 100% conversion of the cells. Conversion was assessed by the expression within the cells of the muscle-specific cytoskeletal protein desmin. We also investigate the effects of galectin-1 on cells of the C2C12 mouse myogenic cell line and on primary mouse myoblasts. Exposing both transformed and primary myoblasts to the lectin resulted in an increase in fusion of cells to the terminally differentiated state in both types of cultures. Galectin-1 does not cause the myogenic conversion of murine muscle-derived fibroblasts.

Animals↗

PubMed2002

Restoration of podosomes and chemotaxis in Wiskott-Aldrich syndrome macrophages following induced expression of WASp.

We used a direct-viewing (Dunn) chemotaxis chamber to analyse the chemotactic responses of human normal and Wiskott-Aldrich syndrome (WAS) macrophages to the cytokine colony stimulating factor-1 (CSF-1). In five patients with classic WAS, where specialised adhesion complexes called podosomes are absent, chemotaxis of macrophages was abolished. The deficient chemotactic responses of WAS macrophages following cytokine stimulation could be correlated with abnormalities in cell polarisation and actin organisation. In a series of cell microinjection studies we found that normal chemotactic responses were restored in WASp macrophages transfected with a full-length human WAS construct. Expression of exogenous WAS protein (WASp) in these cells also restored normal polarised cell morphology and the ability to form podosomes.

Actins↗

PubMed2002

Cell migration in development and disease.

A recent meeting at the Max Delbrück Center in Berlin, Germany provided a forum to discuss the molecular mechanisms of cell migration in a broad range of contexts including chemotaxis, development, immunity, and cancer.

Animals↗

PubMed2002

The involvement of galectin-1 in skeletal muscle determination, differentiation and regeneration.

The dogma that a cell is rigidly committed to one tissue type has been heavily challenged over the past few years with numerous reports of transdifferentiation of cells between different lineages. Cells capable of entering lineages other than that of their tissue of origin have been identified in several diverse tissues. Recently we have focussed on a non-committed myogenic cell within the dermis that is capable, under certain conditions, of expressing muscle specific markers and even fusing to the terminally differentiated stage of muscle cell development. We have identified galectin-1 as being a potent factor implicated in this process. In this review we discuss our findings and consider the involvement of galectin-1 in muscle determination, differentiation and regeneration.

Animals↗

PubMedDate not supplied

The effect of nutritional manipulation on ultra-endurance performance: a case study.

The Atlantic Rowing Race requires teams of two to cover 3,000 nautical miles over 40-90 days. During this ultra-endurance event, competitors require substantial energy intake to meet metabolic requirements; therefore, sufficient physiological and nutritional support is paramount. Two highly trained males (aged 46) engaged in two 14d dietary interventions, with a 14d recovery period in between, to investigate the effect of such interventions on physiological (cardiovascular, cardiorespiratory, and blood-based measures) and performance-based (distance and split time) parameters during an ultra-endurance (2h on 2h off, for 24h) laboratory-based rowing protocol at 60% VO2max. Diet 1: high fat (HF) [60% fat, 30% carbohydrate and 10% protein] and Diet 2: high carbohydrate (HC) [20%, 70% and 10% respectively]. A greater distance was rowed by both subjects (155, 329 m and 134, 797 m vs 130, 089 m and 122, 112 m) with a concomitant reduced heart rate, volume of oxygen uptake, and respiratory exchange ratio, following the HF as opposed to HC dietary intervention. In summary, ultra-endurance performance was enhanced following a 14d HF diet, without apparent implications on liver function and overall lipid profile.

Blood Glucose↗