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The 'lipid raft' hypothesis has been a contentious topic over the past 5 years, with much of the immunology community divided into 'believers' and 'nonbelievers'. The disagreement is due mainly to the inability to observe these membrane domains directly and to the widespread use of experimental approaches of dubious utility. As a lipid raft 'dilettante' who has dabbled in the area over the years, I view the lipid raft model with some skepticism and disinterest because of that confusion. Although progress in the field has helped clarify some of the issues, more work is still needed to formally confirm the lipid raft hypothesis and to reestablish the scientific credibility of this area. [ABSTRACT FROM AUTHOR]

Focuses on the concept of immunological synapse formation as it relates to membrane structure. Requirements for T cell activation; Information on membrane rafts; Early evidences of T cell activation by cross linking.

The role of plasma-membrane microdomains in the organization of signaling proteins has been a controversial topic in T cell signaling. In this issue of Cell, Douglass and Vale (2005) use single-molecule fluorescence to suggest that protein-protein interactions, not detergent insolubility, regulate the assembly of signaling complexes in the plasma membrane. [ABSTRACT FROM AUTHOR]

Reports on the efforts to develop a method using costimulation to build an immunological synapse. How activation of the T cell is the central event in the development of immunity; The role of the T cell receptor (TCR); How efficient T cell activation requires engagement of at least two types of T cell surface receptors; Use of rafts, which are required for T cell activation, in stimulating growth of immunological synapses.

The receptor NKG2D allows natural killer (NK) cells to detect virally infected, stressed, and tumor cells. In human cells, NKG2D signaling is mediated through the associated DAP10 adapter. Here we show that engagement of NKG2D by itself is sufficient to stimulate the formation of the NK immunological synapse (NKIS), with recruitment of NKG2D to the center synapse. Mutagenesis studies of DAP10 revealed that the phosphatidylinositol 3-kinase binding site, but not the Grb2 binding site, was required and sufficient for recruitment of DAP10 to the NKIS. Surprisingly, we found that in the absence of the Grb2 binding site, Grb2 was still recruited to the NKIS. Since the recruitment of Grb2 was dependent on phosphatidylinositol-(3,4,5)-trisphosphate (PIP3), we explored the possibility that recruitment to the NKIS is mediated by a pleckstrin homology (PH) domain-containing binding partner for Grb2. We found that the PH domain of SOS1, but not that of Vav1, was able to be recruited by PIP3. These results provide new insights into the mechanism of immunological synapse formation and also demonstrate how multiple mechanisms can be used to recruit the same signaling proteins to the plasma membrane. [ABSTRACT FROM AUTHOR]

I cells integrate and transduce the key signals necessary to mount an appropriate immune response. To do this, they rely on both secreted factors as well as physical cell-cell contact. Much attention has focused on the organization of proteins at the contact area between a T cell and an antigen-presenting cell, known as the immunological synapse. It has been shown in vitro that proteins segregate into two distinct regions within this contact area, a central area referred to as the c-SMAC, where the I cell receptor and associated signaling molecules are enriched, and a peripheral region called the p-SMAC containing LFA- 1 and the scaffolding protein talin. Whether or not these structures form in vivo and how they function in T cell activation remain issues of great interest, Here, we review recently published work and propose several possible functions for the role of the c-SMAC in T cell activation. [ABSTRACT FROM AUTHOR]

CD2-associated protein (CD2AP) is an adaptor molecule involved in T cell receptor signaling and podocyte homeostasis. CD2AP-deficient mice develop nephrotic syndrome and renal failure caused by glomerulosclerosis. Here we report that increased transforming growth factor-β1 (TGF-β1) expression and apoptosis were present in podocytes at the onset of albuminuria and were followed by depletion of podocytes associated with progressive focal-segmental glomerulosclerosis in CD2AP-/- mice. Conditionally immortalized podocytes derived from CD2AP-/- mice were more susceptible to TGF-β-induced apoptosis compared with CD2AP+/+ podocytes. Reconstitution of CD2AP rescued CD2AP-/- podocytes from TGF-β-induced apoptosis. CD2AP was required for early activation of anti-apoptotic phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase ½ by TGF-β. In contrast, activation of pro-apoptotic p38 MAPK by TGF-β was accelerated and enhanced in the absence of CD2AP. CD2AP was not required for PI3K/AKT activation by insulin and epidermal growth factor, indicating that CD2AP is a selective mediator of anti-apoptotic TGF-β signaling. In summary, we identified CD2AP as a novel mediator for selective activation of survival pathways and repression of apoptosis signaling by TGF-β in podocytes. Together, our in vitro and in vivo findings suggest that TGF-β-induced podocyte apoptosis is an early pathomechanism in mice developing focal-segmental glomerulosclerosis associated with functional impairment of CD2AP. [ABSTRACT FROM AUTHOR]

The specialized epithelial cell of the kidney, the podocyte, has a complex actin-based cytoskeleton. Dynamic regulation of this cytoskeleton is required for efficient barrier function of the kidney. Podocytes are a useful cell type to study the control of the actin cytoskeleton in vivo, because disruption of components of the cytoskeleton results in podocyte damage, cell loss, and a prototypic injury response called focal segmental glomerulosclerosis (FSGS). Searching for actin regulatory proteins that are expressed in podocytes, we identified a RhoA-activated Rac1 GTPase-activating protein (Rac1-GAP), Arhgap24, that was upregulated in podocytes as they differentiated, both in vitro and in vivo. Increased levels of active Rac1 and Cdc42 were measured in Arhgap24 knockdown experiments, which influenced podocyte cell shape and membrane dynamics. Consistent with a role for Arhgap24 in normal podocyte functioning in vivo, sequencing of the ARHGAP24 gene in patients with FSGS identified a mutation that impaired its Rac1-GAP activity and was associated with disease in a family with FSGS. Thus, Arhgap24 contributes to the careful balancing of RhoA and Rac1 signaling in podocytes, the disruption of which may lead to kidney disease. [ABSTRACT FROM AUTHOR]