Biomedical subjects

Andrey Shaw

Publications and source records attributed to Andrey Shaw.

4 recordsLinked to original sources

PubMed2007

CD2AP/CIN85 balance determines receptor tyrosine kinase signaling response in podocytes.

Defects in podocyte signaling are the basis of many inherited glomerular diseases leading to glomerulosclerosis. CD2-associated protein (CD2AP) is highly expressed in podocytes and is considered to play an important role in the maintenance of the glomerular slit diaphragm. Mice deficient for CD2AP (CD2AP(-/-)) appear normal at birth but develop a rapid onset nephrotic syndrome at 3 weeks of age. We demonstrate that impaired intracellular signaling with subsequent podocyte damage is the reason for this delayed podocyte injury in CD2AP(-/-) mice. We document that CD2AP deficiency in podocytes leads to diminished signal initiation and termination of signaling pathways mediated by receptor tyrosine kinases (RTKs). In addition, we demonstrate that CIN85, a paralog of CD2AP, is involved in termination of RTK signaling in podocytes. CIN85 protein expression is increased in CD2AP(-/-) podocytes in vitro. Stimulation of CD2AP(-/-) podocytes with various growth factors, including insulin-like growth factor 1, vascular endothelial growth factor, and fibroblast growth factor, resulted in a significantly decreased phosphatidylinositol 3-kinase/AKT and ERK signaling response. Moreover, increased CIN85 protein is detectable in podocytes in diseased CD2AP(-/-) mice, leading to decreased base-line activation of ERK and decreased phosphorylation after growth factor stimulation in vivo. Because repression of CIN85 protein leads to a restored RTK signaling response, our results support an important role of CD2AP/CIN85 protein balance in the normal signaling response of podocytes.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Immune synapses in T-cell activation.

The contact site between T cells and antigen-presenting cells or T cells and their targets--the immunological synapse--is a highly specialized structure potentially involved in T-cell activation and function. Although many insights have been obtained since the initial description of the immune synapse, recent advances have provided us with a better understanding of mechanisms involved in synapse formation and in the diversity of synapse morphologies. New potential roles for the synapse such as in polarized cytokine secretion or in adaptive control of T-cell activation have been proposed.

Animals↗

PubMed2004

Physiological T cell activation starts and propagates in lipid rafts.

Lipid rafts are plasma membrane compartments enriched in key signaling molecules. We have previously shown that in T lymphocytes anti-CD3 stimulation is insensitive to cholesterol extraction by methyl-beta-cyclodextrin (MbetaCD), suggesting that anti-CD3 induced signal transduction is independent of raft integrity. Here we show that, in contrast to T cell stimulation by anti-CD3 antibodies, T cell activation by a physiological ligand is mediated by signaling events taking place in lipid raft. Indeed, cholesterol depletion by MbetaCD resulted in reduced T cell activation in response to Epstein Barr Virus (EBV)-transformed B cells pulsed with a bacterial superantigen. Moreover, T cell stimulation by pulsed EBV-B cells, but not by anti-CD3 antibodies, induced recruitment of active Lck in detergent-resistant membranes, where the signal transduction is organized and amplified.

Antibodies↗

PubMed2003

Regulation of Fyn through translocation of activated Lck into lipid rafts.

Whether or how the activation of Lck and Fyn during T cell receptor (TCR) signaling is coordinated, and their delivery of function integrated, is unknown. Here we show that lipid rafts function to segregate Lck and Fyn in T cells before activation. Coaggregation of TCR and CD4 leads to Lck activation within seconds outside lipid rafts, followed by its translocation into lipid rafts and the activation of colocalized Fyn. Genetic evidence demonstrates that Fyn activation is strictly dependent on receptor-induced translocation of Lck. These results characterize the interdependence of Lck and Fyn function and establish the spatial and temporal distinctions of their roles in the cellular activation process.

Animals↗