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Biomedical subjects

A S Shaw

Publications and source records attributed to A S Shaw.

At least 19 recordsLinked to original sources
PubMed2003

Ultrasound of non-vascular complications in the post liver transplant patient.

Vascular complications after liver transplantation are readily detected with ultrasound (US) and are well described. Less attention has been paid to non-vascular complications of liver transplantation, which are equally readily detected on US without the need to recourse to further imaging. The types, frequency and features of non-vascular complications are described in this review, with emphasis on biliary complications, types of fluid collections and the features of post-transplant lymphoproliferative disorder.

Ascites↗
PubMed2001

Cutting edge: distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL.

CD28 provides an important costimulatory signal in T cell activation that regulates multiple cellular processes including proliferation and survival. Several signal transduction pathways are activated by CD28; however, the precise biochemical mechanism by which CD28 regulates T cell function remains controversial. Retroviral gene transfer into primary T cells from TCR-transgenic, CD28-deficient mice was used to determine the specific sequences within CD28 that determine function. Discrete regions of the cytoplasmic domain of CD28 were identified that differentially regulate T cell proliferation and induction of the anti-apoptotic protein Bcl-X(L). Mutation of C-terminal proline residues abrogated the proliferative and cytokine regulatory features of CD28 costimulation while preserving Bcl-X(L) induction. Conversely, mutation of residues important in phosphatidylinositol 3-kinase activation partially inhibited proliferation but prevented induction of Bcl-X(L.) Thus the ability of CD28 to regulate proliferation and induction of Bcl-X(L) map to distinct motifs, suggesting independent signaling cascades modulate these biologic effects.

Amino Acid Motifs↗
PubMed2001

CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain.

CD2AP, an adapter protein containing multiple SH3 domains, plays a critical role in kidney function. Mice lacking CD2AP die soon after birth because of kidney failure. In the kidney, CD2AP is expressed in glomerular podocytes, which suggests that it may play a role in a specialized adhesion complex known as the slit diaphragm. One of the major components of the slit diaphragm is nephrin, a podocyte-specific protein. Here we demonstrate that CD2AP localizes to the slit diaphragm in podocytes using immunoelectron microscopy and that nephrin and CD2AP co-immunoprecipitate from a podocyte cell line. The specificity of this interaction was verified by mapping studies, which demonstrated that a novel domain at the C terminus of CD2AP interacts with the C-terminal portion of the nephrin cytoplasmic domain. These studies lend further support to the idea that CD2AP plays a role in the structural integrity of the slit diaphragm.

Adaptor Proteins, Signal Transducing↗
PubMed2001

FERMing up the synapse.

The immunological synapse is characterized by the reorganization of membrane proteins at the immunological synapse. Active cytoskeletal mechanisms are involved in recruiting the TCR, accessory molecules, and the integrin LFA-1 to the contact area. Other molecules like CD43 are excluded from the contact area, but the mechanism of exclusion is unknown. Three papers in this issue of Immunity demonstrate that CD43 exclusion involves the ERM family of cytoskeletal proteins.

Animals↗
PubMed2001

Environmental control of immunological synapse formation and duration.

The coordination of T-cell migration and antigen recognition is crucial for an effective immune response. We have proposed that this coordination is achieved by formation of an immunological synapse between the T cell and the antigen-presenting cell (APC). Our view contrasts with the serial encounter model also proposed in this issue of Trends in Immunology, which is based on transient T cell-APC interactions when surrounded by collagen. Here, we propose a model that reconciles immunological synapse formation and serial encounters based on environmental control of immunological synapse formation.

Animals↗
PubMed2001

The immunological synapse and CD28-CD80 interactions.

According to the two-signal model of T cell activation, costimulatory molecules augment T cell receptor (TCR) signaling, whereas adhesion molecules enhance TCR-MHC-peptide recognition. The structure and binding properties of CD28 imply that it may perform both functions, blurring the distinction between adhesion and costimulatory molecules. Our results show that CD28 on naïve T cells does not support adhesion and has little or no capacity for directly enhancing TCR-MHC-peptide interactions. Instead of being dependent on costimulatory signaling, we propose that a key function of the immunological synapse is to generate a cellular microenvironment that favors the interactions of potent secondary signaling molecules, such as CD28.

B7-1 Antigen↗
PubMed2001

CD2-associated protein and the kidney.

During the past 3 years there have been significant advances in our understanding of the biology of the glomerular podocyte. In particular, two proteins, CD2-associated protein and nephrin, have been identified as critical podocyte proteins that are both required for normal glomerular filtration. In addition to supporting the idea that the slit diaphragm plays a crucial role in glomerular function, these results suggest novel insights into the pathogenesis of glomerular diseases. The present review addresses these recent advances and discusses the implications of the findings.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The immunological synapse.

The adaptive immune response is initiated by the interaction of T cell antigen receptors with major histocompatibility complex molecule-peptide complexes in the nanometer scale gap between a T cell and an antigen-presenting cell, referred to as an immunological synapse. In this review we focus on the concept of immunological synapse formation as it relates to membrane structure, T cell polarity, signaling pathways, and the antigen-presenting cell. Membrane domains provide an organizational principle for compartmentalization within the immunological synapse. T cell polarization by chemokines increases T cell sensitivity to antigen. The current model is that signaling and formation of the immunological synapse are tightly interwoven in mature T cells. We also extend this model to natural killer cell activation, where the inhibitory NK synapse provides a striking example in which inhibition of signaling leaves the synapse in its nascent, inverted state. The APC may also play an active role in immunological synapse formation, particularly for activation of naïve T cells.

Animals↗
PubMed2001

Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin.

NPHS2 was recently identified as a gene whose mutations cause autosomal recessive steroid-resistant nephrotic syndrome. Its product, podocin, is a new member of the stomatin family, which consists of hairpin-like integral membrane proteins with intracellular NH(2)- and COOH-termini. Podocin is expressed in glomerular podocytes, but its subcellular distribution and interaction with other proteins are unknown. Here we show, by immunoelectron microscopy, that podocin localizes to the podocyte foot process membrane, at the insertion site of the slit diaphragm. Podocin accumulates in an oligomeric form in lipid rafts of the slit diaphragm. Moreover, GST pull-down experiments reveal that podocin associates via its COOH-terminal domain with CD2AP, a cytoplasmic binding partner of nephrin, and with nephrin itself. That podocin interacts with CD2AP and nephrin in vivo is shown by coimmunoprecipitation of these proteins from glomerular extracts. Furthermore, in vitro studies reveal direct interaction of podocin and CD2AP. Hence, as with the erythrocyte lipid raft protein stomatin, podocin is present in high-order oligomers and may serve a scaffolding function. We postulate that podocin serves in the structural organization of the slit diaphragm and the regulation of its filtration function.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Coordinate regulation of T cell activation by CD2 and CD28.

T cell activation requires co-engagement of the TCR with accessory and costimulatory molecules. However, the exact mechanism of costimulatory function is unknown. Mice lacking CD2 or CD28 show only mild deficits, demonstrating that neither protein is essential for T cell activation. In this paper we have generated mice lacking both CD2 and CD28. T cells from the double-deficient mice have a profound defect in activation by soluble anti-CD3 Ab and Ag, yet remain responsive to immobilized anti-CD3. This suggests that CD2 and CD28 may function together to facilitate interactions of the T cell and APC, allowing for efficient signal transduction through the TCR.

Animals↗
PubMed2000

Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition.

T cell antigen recognition is accompanied by cytoskeletal polarization towards the APC and large-scale redistribution of cell surface molecules into 'supramolecular activation clusters' (SMACs), forming an organized contact interface termed the 'immunological synapse' (IS). Molecules are arranged in the IS in a micrometer scale bull's eye pattern with a central accumulation of TCR/peptide-MHC (the cSMAC) surrounded by a peripheral ring of adhesion molecules (the pSMAC). We propose that segregation of cell surface molecules on a much smaller scale initiates TCR triggering, which drives the formation of the IS by active transport processes. IS formation may function as a checkpoint for full T cell activation, integrating information on the presence and quality of TCR ligands and the nature and activation state of the APC.

Animals↗
PubMed2000

Signal transduction: hanging on a scaffold.

Recent data concerning scaffolding proteins profoundly challenge our conceptions of multicomponent signal transduction systems. Recent studies of the phototransduction system in Drosophila suggest two points. First, scaffolding markedly limits the possibilities for signal amplification. Second, the methods generally available to study signal transduction may be too crude to assess the in vivo roles of scaffolds. Studies of the mitogen-activated protein kinase pathway scaffold, Ste5, indicate functions beyond that of a passive structural element. Finally, the identification of new mitogen-activated protein kinase pathway scaffolds suggests the existence of multiple 'signalosomes' or 'transducisomes'.

Adaptor Proteins, Signal Transducing↗
PubMed2000

CD28 and the tyrosine kinase lck stimulate mitogen-activated protein kinase activity in T cells via inhibition of the small G protein Rap1.

Proliferation of T cells via activation of the T-cell receptor (TCR) requires concurrent engagement of accessory costimulatory molecules to achieve full activation. The best-studied costimulatory molecule, CD28, achieves these effects, in part, by augmenting signals from the TCR to the mitogen-activated protein (MAP) kinase cascade. We show here that TCR-mediated stimulation of MAP kinase extracellular-signal-regulated kinases (ERKs) is limited by activation of the Ras antagonist Rap1. CD28 increases ERK signaling by blocking Rap1 action. CD28 inhibits Rap1 activation because it selectively stimulates an extrinsic Rap1 GTPase activity. The ability of CD28 to stimulate Rap1 GTPase activity was dependent on the tyrosine kinase Lck. Our results suggest that CD28-mediated Rap1 GTPase-activating protein activation can help explain the augmentation of ERKs during CD28 costimulation.

Animals↗
PubMed2000

CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere.

CD2-associated protein (CD2AP) is an adapter molecule that can bind to the cytoplasmic domain of nephrin, a component of the glomerular slit diaphragm. Mice lacking CD2AP exhibit a congenital nephrotic syndrome characterized by extensive foot process effacement, suggesting that CD2AP-nephrin interactions are critical to maintaining slit diaphragm function. We have examined the patterns of expression of both CD2AP and nephrin in developing mouse and human kidney. Both proteins were first detected in developing podocytes at the capillary loop stage of glomerulogenesis and eventually became concentrated near the glomerular basement membrane. CD2AP was also observed diffusely in collecting duct and apically in many cells of proximal and distal tubule. Kidneys from Cd2ap -/- mice initially exhibited normal nephrin localization, but as the mice aged and foot processes became effaced, nephrin disappeared. In laminin-beta(2) mutant mice exhibiting nephrotic syndrome, CD2AP in glomeruli was aberrantly localized in a primarily punctate pattern. Extensive extrarenal expression of CD2AP was observed in endothelial and epithelial cells, in many cases with a specific subcellular localization. Together, these results suggest that CD2AP is not only involved in maintaining the slit diaphragm but may also have a general role in maintaining specialized subcellular architecture. The severity of kidney disease in Cd2ap mutant mice may have eclipsed manifestation of defects in other tissues.

Adaptor Proteins, Signal Transducing↗
PubMed2000

CD28 and T cell co-stimulation.

Over the last decade the concept of T cell co-stimulation has emerged to take a central role in the process of T cell activation. However, the exact definition of co-stimulation is still unclear. In this review, we re-examine the concept of co-stimulation. We suggest that while co-stimulation is important, there is little evidence to link co-stimulation with T cell anergy. We then suggest a framework for studying co-stimulation. Focusing on recent advances in our understanding of CD28, we discuss four areas of T cell activation where co-stimulation may play a role.

Animals↗
PubMed1999

Congenital nephrotic syndrome in mice lacking CD2-associated protein.

CD2-associated protein (CD2AP) is an 80-kilodalton protein that is critical for stabilizing contacts between T cells and antigen-presenting cells. In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells. Knockout mice exhibited defects in epithelial cell foot processes, accompanied by mesangial cell hyperplasia and extracellular matrix deposition. Supporting a role for CD2AP in the specialized cell junction known as the slit diaphragm, CD2AP associated with nephrin, the primary component of the slit diaphragm.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Proline residues in CD28 and the Src homology (SH)3 domain of Lck are required for T cell costimulation.

The Src family tyrosine kinases Lck and Fyn are critical for signaling via the T cell receptor. However, the exact mechanism of their activation is unknown. Recent crystal structures of Src kinases suggest that an important mechanism of kinase activation is via engagement of the Src homology (SH)3 domain by proline-containing sequences. To test this hypothesis, we identified several T cell membrane proteins that contain potential SH3 ligands. Here we demonstrate that Lck and Fyn can be activated by proline motifs in the CD28 and CD2 proteins, respectively. Supporting a role for Lck in CD28 signaling, we demonstrate that CD28 signaling in both transformed and primary T cells requires Lck as well as proline residues in CD28. These data suggest that Lck plays an essential role in CD28 costimulation.

Alanine↗