Cytoskeletal Modulation of Lipid Interactions Regulates Lck Kinase Activity

Chichili, Gurunadh R.; Cail, Robert C.; Rodgers, William

doi:10.1074/jbc.m111.320747

Cited by 10 publications

(8 citation statements)

References 54 publications

(47 reference statements)

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“…Using fluorescent probes C 16 Dil and C 16 DiO, which incorporate to lipid ordered regions at the plasma membrane 26 , we found the FRET signal from C 16 Dil and C 16 DiO (Figure S12) was drastically elevated in Cd82-null ECs and such elevation could be abrogated by raft disrupter filipin (Figure 6C), suggesting higher order of lipid rafts in Cd82-null EC membrane. Consistently, the surface levels of gangliosides GM1, GM2, and GM3 were upregulated in Cd82-null ECs (Figure 6D).…”

Section: Resultsmentioning

confidence: 99%

CD82 Restrains Pathological Angiogenesis by Altering Lipid Raft Clustering and CD44 Trafficking in Endothelial Cells

et al. 2014

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Background Angiogenesis is crucial for many pathological processes and becomes a therapeutic strategy against diseases ranging from inflammation to cancer. The regulatory mechanism of angiogenesis remains unclear. Although tetraspanin CD82 is widely expressed in various endothelial cells (ECs), its vascular function is unknown. Methods and Results Angiogenesis was examined in Cd82-null mice with in vivo and ex vivo morphogenesis assays. Cellular functions, molecular interactions, and signaling were analyzed in Cd82-null ECs. Angiogenic responses to various stimuli became markedly increased upon Cd82 ablation. Major changes of Cd82-null ECs were enhanced migration and invasion, likely resulting from the upregulated expression of cell adhesion molecules (CAMs) such as CD44 and integrins at the cell surface and subsequently elevated outside-in signaling. Gangliosides, lipid raft clustering, and CD44-membrane microdomain interactions were increased in the plasma membrane of Cd82-null ECs, leading to less clathrin-independent endocytosis and then more surface presence of CD44. Conclusions Our study reveals that CD82 restrains pathological angiogenesis by inhibiting EC movement, lipid raft clustering and CAM trafficking modulate angiogenic potential, and the perturbation of CD82-ganglioside-CD44 signaling attenuates angiogenesis.

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Section: Resultsmentioning

confidence: 99%

CD82 Restrains Pathological Angiogenesis by Altering Lipid Raft Clustering and CD44 Trafficking in Endothelial Cells

et al. 2014

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“…For Lck, this is represented by phospho-Tyr 394 (pTyr 394 ). In Jurkat cells, pTyr 394 accounts for 90% of the signal from immunoblotting lysates with the kinase domain-specific phosphotyrosine antibody (33). Comparing conjugates containing Jurkat cells with those with CD45-deficient J45.01 (Supplemental Figure 1D), CD45 expression reduced by 30% the pTyr 394 signal where the T cell contacted a B cell (Supplemental Figure 1D and Figure 6C).…”

Section: Resultsmentioning

confidence: 99%

“…Rafts are cholesterol-dependent lipid heterogeneities that serve as a membrane platform for cell signaling and signal regulation (17, 33, 43–47). Similarly, our data show where signals for AIS formation are compartmentalized to rafts.…”

Section: Discussionmentioning

confidence: 99%

CD28 Sensitizes TCR Ca2+ Signaling during Ag-Independent Polarization of Plasma Membrane Rafts

Byrum

Komen

Rodgers

2013

The Journal of Immunology

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T cells become polarized during initial interactions with an APC to form an antigen-independent synapse (AIS) composed of membrane rafts, TCR, and TCR-proximal signaling molecules. AISs occur temporally before TCR triggering, but their role in downstream TCR signaling is not understood. Using both human and murine model systems, we studied the signals that activate AIS formation, and the effect of these signals on TCR-dependent responses. We show that CD28 produces AISs detectable by spinning disc confocal microscopy seconds following initial interactions between the T cell and APC. AIS formation by CD28 coincided with co-stimulatory signaling, evidenced by a cholesterol-sensitive activation of the MAP kinase ERK that potentiated Ca2+ signaling in response to CD3 crosslinking. CD45 also enriched in AISs, but to modulate Src kinase activity, since localization of CD45 at the cell interface reduced the activation of proximal Lck. In summary, we show that signaling by CD28 during first encounters between the T cell and APC both sensitizes TCR Ca2+ signaling by an Erk-dependent mechanism, and drives formation of an AIS that modulates the early signaling until TCR triggering occurs. Thus, early Ag-independent encounters are an important window for optimizing T cell responses to antigen by CD28.

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“…The actin cytoskeleton might be crucial in transporting TCRs into the kinase-rich lipid rafts and maintaining the lipid raft environment. Evidence to support the role of actin in this mechanism includes studies in which disruption of the actin cytoskeleton leads to disappearance of lipid rafts and CD45 in the immunological synapse (Valensin et al, 2002;Chichili et al, 2010;Chichili et al, 2012). However, a recent study suggests that formation of lipid rafts is not sufficient for Lck clustering (Rossy et al, 2013).…”

Section: Actin In the Kinetic Segregation Modelmentioning

confidence: 99%

Modulation of T cell signaling by the actin cytoskeleton

Smoligovets

Groves

2013

Journal of Cell Science

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SummaryThe actin cytoskeleton provides a dynamic framework to support membrane organization and cellular signaling events. The importance of actin in T cell function has long been recognized to go well beyond the maintenance of cell morphology and transport of proteins. Over the past several years, our understanding of actin in T cell activation has expanded tremendously, in part owing to the development of methods and techniques to probe the complex interplay between actin and T cell signaling. On the one hand, biochemical methods have led to the identification of many key cytoskeleton regulators and new signaling pathways, whereas, on the other, the combination of advanced imaging techniques and physical characterization tools has allowed the spatiotemporal investigation of actin in T cell signaling. All those studies have made a profound impact on our understanding of the actin cytoskeleton in T cell activation. Many previous reviews have focused on the biochemical aspects of the actin cytoskeleton. However, here we will summarize recent studies from a biophysical perspective to explain the mechanistic role of actin in modulating T cell activation. We will discuss how actin modulates T cell activation on multiple time and length scales. Specifically, we will reveal the distinct roles of the actin filaments in facilitating TCR triggering, orchestrating 'signalosome' assembly and transport, and establishing protein spatial organization in the immunological synapse.

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Cytoskeletal Modulation of Lipid Interactions Regulates Lck Kinase Activity

Cited by 10 publications

References 54 publications

CD82 Restrains Pathological Angiogenesis by Altering Lipid Raft Clustering and CD44 Trafficking in Endothelial Cells

CD82 Restrains Pathological Angiogenesis by Altering Lipid Raft Clustering and CD44 Trafficking in Endothelial Cells

CD28 Sensitizes TCR Ca2+ Signaling during Ag-Independent Polarization of Plasma Membrane Rafts

Modulation of T cell signaling by the actin cytoskeleton

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