LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways

Sommers, Connie L.; Samelson, Lawrence E.; Love, Paul E.

doi:10.1002/bies.10384

Cited by 69 publications

(60 citation statements)

References 50 publications

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“…Phosphorylated LAT is a docking site for signaling proteins that include Grb-2, phospholipase C␥, and phosphatidylinositol 3-kinase. Recruitment of these proteins to the membrane, through binding to LAT, is required for their activation (46).…”

mentioning

confidence: 99%

Palmitoylation and Intracellular Domain Interactions Both Contribute to Raft Targeting of Linker for Activation of T Cells

Shogomori

Hammond

Ostermeyer-Fay

et al. 2005

Journal of Biological Chemistry

120

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Some transmembrane proteins must associate with lipid rafts to function. However, even if acylated, transmembrane proteins should not pack well with ordered raft lipids, and raft targeting is puzzling. Acylation is necessary for raft targeting of linker for activation of T cells (LAT). To determine whether an acylated transmembrane domain is sufficient, we examined raft association of palmitoylated and nonpalmitoylated LAT transmembrane peptides in lipid vesicles by a fluorescence quenching assay, by microscopic examination, and by association with detergent-resistant membranes (DRMs). All three assays detected very low raft association of the nonacylated LAT peptide. DRM association was the same as a control random transmembrane peptide. Acylation did not measurably enhance raft association by the first two assays but slightly enhanced DRM association. The palmitoylated LAT peptide and a FLAG-tagged LAT transmembrane domain construct expressed in cells showed similar DRM association when both were reconstituted into mixed vesicles (containing cell-derived proteins and lipids and excess artificial raft-forming lipids) before detergent extraction. We conclude that the acylated LAT transmembrane domain has low inherent raft affinity. Full-length LAT in mixed vesicles associated better with DRMs than the peptide. However, cells appeared to contain two pools of LAT, with very different raft affinities. Since some LAT (but not the transmembrane domain construct) was isolated in a protein complex, and the Myc-and FLAG-tagged forms of LAT could be mutually co-immunoprecipitated, oligomerization or interactions with other proteins may enhance raft affinity of one pool of LAT. We conclude that both acylation and other factors, possibly proteinprotein interactions, target LAT to rafts.Recent years have seen an explosion of interest in membrane microdomains called lipid rafts (1-3). Rafts have been implicated in processes as diverse as signal transduction (1, 4), membrane trafficking (5, 6), and apoptosis (7). In addition, many pathogenic viruses and bacteria hijack host cell rafts during infection (8 -10). In all of these cases, function depends on selective enrichment of a subset of membrane proteins in rafts. For this reason, it is important to determine how proteins are targeted to rafts.A key feature of raft structure is the tight packing of lipid acyl chains. Raft lipids are probably in the liquid-ordered (l o ) 1 phase, in which lipid acyl chains are extended and ordered (11,12). Many proteins are targeted to rafts by their favorable association with these ordered lipids. For example, raft proteins such as glycosylphosphatidylinositol-anchored proteins, Src family kinases, and heterotrimeric G protein ␣ subunits are linked to saturated acyl chains, which partition well into rafts. Because of this tight acyl chain packing, raft lipids and proteins are insoluble in nonionic detergents and can be isolated from cell lysates as DRMs. Although DRM association of a protein may not provide a quantitative measure of its asso...

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mentioning

confidence: 99%

Palmitoylation and Intracellular Domain Interactions Both Contribute to Raft Targeting of Linker for Activation of T Cells

Shogomori

Hammond

Ostermeyer-Fay

et al. 2005

Journal of Biological Chemistry

120

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“…ZAP-70 then phosphorylates the downstream T cell signalling molecules, LAT (linker for the activation of T cells) (Zhang et al, 1998) and SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) (Bubeck Wardenburg et al, 1996;Samelson, 2002). Phosphorylated LAT complexes with SLP-76 via the adaptor proteins Gads and Grb2 and acts as a scaffold for the recruitment of additional signalling proteins, promoting downstream activation events (Liu et al, 1999;Sommers et al, 2004). PLC-(Phosphoinositide phospholipase C ) recruited to phosphorylated SLP-76, catalyzes the breakdown of the membranal phospholipid Phosphatidylinositol 4,5-bisphosphate (PIP2) into the secondary messengers, diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3) (Beach et al, 2007;Ebinu et al, 1998).…”

Section: Leukocytes and Their Regulationmentioning

confidence: 99%

Stoichiometry of Signalling Complexes in Immune Cells: Regulation by the Numbers

Noy¹,

Reicher²,

Barda‐Saad³

2012

Stoichiometry and Research - The Importance of Quantity in Biomedicine

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“…FcRβ/FcRγ ITAMs and Syk were phopshorylated as in wt cells. These observations suggested that LAT primarily serves as a coupling molecule between immunoreceptors and intracellular signaling pathways leading to cellular responses (Sommers et al, 2004). LAT contains many tyrosines (9 in mice, 10 in humans) in its intracytoplasmic domain (Weber et al, 1998;Zhang et al, 1998a).…”

Section: Organization Of Fcr Signaling Complexes By Adapter Proteinsmentioning

confidence: 99%

“…LAT has been first understood to organize signalosomes generated by activating receptors and to couple them with downstream signaling pathways leading to cellular responses (Sommers et al, 2004). LAT is critical for TCR signals involved in early T cell differentiation and, indeed, LAT-deficient mice display an arrest in thymocyte development with a block in both TCRαβ and γδ T cell differentiation (Zhang et al, 1999).…”

Section: Latmentioning

confidence: 99%

Negative Signaling in Fc Receptor Complexes

Daëron

Lesourne

2006

Advances in Immunology

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Cell activation results from the transient displacement of an active balance between positive and negative signaling. This displacement depends in part on the engagement of cell surface receptors by extracellular ligands. Among these are Receptors for the Fc portion of immunoglobulins (FcRs). FcRs are widely expressed by cells of hematopoietic orign. When binding antibodies, FcRs provide these cells with immunoreceptors capable of triggering numerous biological responses in response to specific antigen. FcR-dependent cell activation is regulated by negative signals which are generated together with positive signals within signalosomes that form upon FcR engagement. Many molecules involved in positive signaling, including the FcRβ subunit, the src kinase lyn, the cytosolic adapter Grb2, the transmembrane adapters LAT and NTAL, are indeed also involved in negative signaling. A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1. Several layers of negative regulation operate sequentially as FcRs are engaged by extracellular ligands of increasing valency. A background protein tyrosine phosphatasedependent negative regulation maintains cells in a « resting » state. SHIP1-dependent negative regulation can be detected as soon as high-affinity FcRs are occupied by antibodies in the absence of antigen. It increases when activating FcRs are engaged by multivalent ligands and, further when FcR aggregation increases, accounting for the bell-shaped dose-response curve observed in excess of ligand. Finally, F-actin skeleton-associated high-molecular weight SHIP1, recruited to phopshorylated ITIMs, concentrates in signaling complexes when activating FcRs are coengaged with inhibitory FcRs by immune complexes. Based on these data, activating and inhibitory FcRs could be used for new therapeutic approaches of immune disorders.

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LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways

Cited by 69 publications

References 50 publications

Palmitoylation and Intracellular Domain Interactions Both Contribute to Raft Targeting of Linker for Activation of T Cells

Palmitoylation and Intracellular Domain Interactions Both Contribute to Raft Targeting of Linker for Activation of T Cells

Stoichiometry of Signalling Complexes in Immune Cells: Regulation by the Numbers

Negative Signaling in Fc Receptor Complexes

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