The Linker for Activation of T Cells (LAT) Signaling Hub: From Signaling Complexes to Microclusters

Balagopalan, Lakshmi; Kortum, Robert L.; Coussens, Nathan P.; Barr, Valarie A.; Samelson, Lawrence E.

doi:10.1074/jbc.r115.665869

Cited by 110 publications

(128 citation statements)

References 67 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…In unstimulated cells, LAT is organized in nanocluster-scale units that are composed of 5 molecules or less. After TCR activation, these proteins oligomerize into microcluster-scale units that are composed of >25 molecules (49–51, 53–55). However, there is a disconnect between SLP-76- and LAT-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters

et al. 2018

View full text Add to dashboard Cite

Glycerol monolaurate (GML) is a monoglyceride with potent antimicrobial properties that suppresses T cell receptor (TCR)-induced signaling and T cell effector function. Actin rearrangement is needed for the interaction of T cells with antigen presenting cells and for migration to sites of infection. Because of the critical role actin rearrangement plays in T cell effector function, we analyzed the effect of GML on the rearrangement of the actin cytoskeleton after TCR activation. We found that GML-treated human T cells were less adherent than untreated T cells and did not form actin ring structures, but instead developed numerous inappropriate actin-mediated filopodia. The formation of these filopodia was not due to disruption of TCR-proximal regulators of actin or microtubule polymerization. Instead, total internal reflection fluorescence microscopy demonstrated mislocalization of actin nucleation protein Arp2 microclusters, but not those containing the adaptor proteins SLP-76 and WASp, or the actin nucleation protein ARPC3, which are necessary for TCR-induced actin rearrangement. Additionally, SLP-76 microclusters colocalized with WASp and WAVE microclusters, but not LAT. Together, our data suggest that GML alters actin cytoskeletal rearrangements and identify diverse functions for GML as a T cell-suppressive agent.

show abstract

Section: Discussionmentioning

confidence: 99%

Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Grb2 additionally has two SH3 domains, which bind to the proline-rich regions in the C-terminal domain of the nucleotide exchange factor, Son of Sevenless (SOS) (14). A single SOS molecule can associate with at least two Grb2 molecules (15), enabling the LAT:Grb2:SOS interactions to form an extended network assembly on membranes upon LAT phosphorylation (15)(16)(17)(18) (Fig. 1).…”

mentioning

confidence: 99%

Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS

Huang

Yan

Lin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

174

View full text Add to dashboard Cite

The assembly of cell surface receptors with downstream signaling molecules is a commonly occurring theme in multiple signaling systems. However, little is known about how these assemblies modulate reaction kinetics and the ultimate propagation of signals. Here, we reconstitute phosphotyrosine-mediated assembly of extended linker for the activation of T cells (LAT):growth factor receptor-bound protein 2 (Grb2):Son of Sevenless (SOS) networks, derived from the T-cell receptor signaling system, on supported membranes. Single-molecule dwell time distributions reveal two, well-differentiated kinetic species for both Grb2 and SOS on the LAT assemblies. The majority fraction of membrane-recruited Grb2 and SOS both exhibit fast kinetics and single exponential dwell time distributions, with average dwell times of hundreds of milliseconds. The minor fraction exhibits much slower kinetics, extending the dwell times to tens of seconds. Considering this result in the context of the multistep process by which the Ras GEF (guanine nucleotide exchange factor) activity of SOS is activated indicates that kinetic stabilization from the LAT assembly may be important. This kinetic proofreading effect would additionally serve as a stochastic noise filter by reducing the relative probability of spontaneous SOS activation in the absence of receptor triggering. The generality of receptor-mediated assembly suggests that such effects may play a role in multiple receptor proximal signaling processes.signal transduction | protein assembly | kinetic proofreading | membrane dwell time | single molecule

show abstract

“…In contrast to these large, irreversible amyloid fibrils in the cytosol, polymers of inhibitory KIR at immunological synapses form at the cell surface, and dissociate in the absence of zinc. The discovery of zinc-dependent KIR filaments at inhibitory NK cell immunological synapses expands on the recent paradigm of functional higher-order assemblies of molecules that can regulate the amplitude, time and location of signals (Balagopalan et al, 2015; Cai and Chen, 2014; Wu, 2013). Finally, the ZiPR mechanism may have relevance beyond inhibitory immunological synapses to receptors in other systems, such as synaptic plasticity in the cerebral cortex, which is regulated by release of zinc from synaptic vesicles (Pan et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Zinc-Induced Polymerization of Killer-Cell Ig-like Receptor into Filaments Promotes Its Inhibitory Function at Cytotoxic Immunological Synapses

et al. 2016

View full text Add to dashboard Cite

SUMMARY The inhibitory function of killer cell immunoglobulin-like receptors (KIR) that bind HLA-C and block activation of human natural killer (NK) cells is dependent on zinc. We report that zinc induced the assembly of soluble KIR into filamentous polymers, as detected by electron microscopy, which depolymerized after zinc chelation. Similar KIR filaments were isolated from lysates of cells treated with zinc, and membrane protrusions enriched in zinc were detected on whole cells by scanning electron microscopy and imaging mass spectrometry. Two independent mutations in the extracellular domain of KIR, away from the HLA-C binding site, impaired zinc-driven polymerization and inhibitory function. KIR filaments formed spontaneously, without addition of zinc, at functional inhibitory immunological synapses of NK cells with HLA-C+ cells. Adding to the recent paradigm of signal transduction through higher-order molecular assemblies, zinc-induced polymerization of inhibitory KIR represents an unusual mode of signaling by a receptor at the cell surface.

show abstract

The Linker for Activation of T Cells (LAT) Signaling Hub: From Signaling Complexes to Microclusters

Cited by 110 publications

References 67 publications

Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters

Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters

Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS

Zinc-Induced Polymerization of Killer-Cell Ig-like Receptor into Filaments Promotes Its Inhibitory Function at Cytotoxic Immunological Synapses

Contact Info

Product

Resources

About