c-Cbl-Mediated Regulation of LAT-Nucleated Signaling Complexes

Balagopalan, Lakshmi; Barr, Valarie A.; Sommers, Connie L.; Barda‐Saad, Mira; Goyal, Amrita; Isakowitz, Matthew S.; Samelson, Lawrence E.

doi:10.1128/mcb.00467-07

Cited by 99 publications

(146 citation statements)

References 54 publications

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“…In addition, consistent with its role as an E3-ubiquitin ligase in several signaling systems, c-Cbl has been implicated in ubiquitylation of the TCRz and CD3d chains of the TCR as well as the signaling proteins ZAP-70, LAT, PLC-g1, PI3K, Vav, and PKC-u in T cells (Weissman 2001;Duan et al 2004;Balagopalan et al 2007). The effects of LATubiquitylation on controlling internalization and cellular LAT levels are discussed in the imaging section later.…”

Section: Plc-g1 Binds Y132 Of Lat and Mediates Transcriptional Activamentioning

confidence: 86%

“…Microclusters play a predominant role in the generation of sustained signals. Current models also indicate that cluster centralization plays an important role in signal termination and that the cSMAC is a site both for TCR down-regulation yet also for amplification of weak signals (Lee et al 2003;Mossman et al 2005;Varma et al 2006;Balagopalan et al 2007;Cemerski et al 2008;Nguyen et al 2008). A recent study using a photoactivatable agonist in a lipid bilayer system has provided even greater precision in the temporal resolution of these events and demonstrated that adapters are recruited to microclusters within four seconds (Huse et al 2007).…”

Section: Lat Microclusters: Sites Of Nucleation Of Signaling Complexesmentioning

confidence: 99%

“…The adapters LAT and SLP-76 departed the initial complexes in what appeared to be small vesicular intermediates and dissipated soon thereafter (Bunnell et al 2002). Recent studies have shown that microclusters containing LAT and SLP-76 undergo endocytosis upon TCR stimulation Balagopalan et al 2007). SLP-76 is endocytosed in a lipid-raft dependent pathway that requires the association of the endocytic machinery with ubiquitylated proteins.…”

Section: Dynamics Of Lat Clusters Lat Internalization and Lat Ubiquimentioning

confidence: 99%

“…SLP-76 is endocytosed in a lipid-raft dependent pathway that requires the association of the endocytic machinery with ubiquitylated proteins. LAT endocytosis is a complex process and internalized LAT is found in several intracellular compartments (Bonello et al 2004;Brignatz et al 2005;Balagopalan et al 2007). Insights into the molecular mechanisms that regulate endocytosis of microcluster-associated proteins came from studies in which internalization of the microclusters was inhibited.…”

Section: Dynamics Of Lat Clusters Lat Internalization and Lat Ubiquimentioning

confidence: 99%

“…Palmitoylation of LAT is necessary for LAT function (Lin et al 1999;Zhang et al 1999a), but the role of palmitoylation in specific localization of LAT within the plasma membrane has been controversial and is discussed below. More recently, studies have shown that LAT is also subject to ubiquitylation (Brignatz et al 2005;Balagopalan et al 2007), a modification that might be involved in activation-induced internalization of LAT complexes and regulation of LAT protein levels. Inspection of LAT amino acid sequence reveals two lysines (K52 and K204 in human LAT), which might serve as potential sites for ubiquitylation.…”

Section: Cloning and Structural Features Of Latmentioning

confidence: 99%

See 4 more Smart Citations

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

153

184

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The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.

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Section: Plc-g1 Binds Y132 Of Lat and Mediates Transcriptional Activamentioning

confidence: 86%

Section: Lat Microclusters: Sites Of Nucleation Of Signaling Complexesmentioning

confidence: 99%

Section: Dynamics Of Lat Clusters Lat Internalization and Lat Ubiquimentioning

confidence: 99%

Section: Dynamics Of Lat Clusters Lat Internalization and Lat Ubiquimentioning

confidence: 99%

Section: Cloning and Structural Features Of Latmentioning

confidence: 99%

See 3 more Smart Citations

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

153

184

View full text Add to dashboard Cite

show abstract

The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation

Bartelt

Houtman

2012

WIREs Mechanisms of Disease

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T cells are essential for the adaptive immune response to pathogens. However, dysfunctional T cell activity has been implicated in numerous diseases, including the failure of organ transplants, allergic reactions, asthma, autoimmune disorders, and coronary artery disease. T cell responses to pathogens require the induction of the primary activating receptor, the T cell receptor (TCR), along with other costimulatory and adhesion receptors. Signal transduction pathways activated downstream of these receptors drive T cell responses required for the immune response and disease progression. A key question in our understanding of the mechanism of T cell activation is how signalling pathways emanating from multiple receptors integrate together to alter T cell effector functions. One integration node for intracellular signalling is the membrane-associated adaptor protein linker for the activation of T cells or LAT. Upon stimulation of the TCR and other receptors, LAT is phosphorylated at several tyrosines residues on its cytoplasmic tail. This leads to the binding of SH2-domain containing proteins and their associated molecules and the formation of large multiprotein complexes. These dynamic and highly regulated signalling complexes facilitate the production of second messengers, activate downstream pathways, induce actin cytoskeleton polymerization, and stimulate the activity of multiple transcription factors. Thus, signalling pathways from several receptors feed into LAT, which then integrates this information and selectively induces pathways critical for T cell activation and the adaptive immune response.

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The Immunological Synapse, TCR Microclusters, and T Cell Activation

Yokosuka

Saito²

2009

Current Topics in Microbiology and Immunology

113

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T cell activation begins with the interaction between an antigen-specific T cell and an antigen-presenting cell (APC). This interaction results in the formation of the immunological synapse, which had been considered to be responsible for antigen recognition and T cell activation. Recent advances in imaging analysis have provided new insights into T cell activation. The T cell receptor (TCR) microclusters, TCRs, kinases, and adaptors are generated upon antigen recognition at the interfaces between the T cells and the APCs and serve as a fundamental signaling unit for T cell activation. CD28-mediated costimulation is also found to be regulated by the formation of microclusters. Therefore, the dynamic regulations of TCR and CD28 microcluster formation, migration, and interaction are the key events for the initiation of T cell-mediated immune responses. Comprehensive analyses of the composition and characteristics of the TCR microcluster have identified its dynamic features. This review will outline new discoveries of the microclusters and its related concept in T cell activation.

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c-Cbl-Mediated Regulation of LAT-Nucleated Signaling Complexes

Cited by 99 publications

References 54 publications

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation

The Immunological Synapse, TCR Microclusters, and T Cell Activation

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