The role of adaptor proteins in lymphocyte activation

Togni, Mauro; Lindquist, Jon; Gerber, Annegret; Kölsch, Uwe; Hamm-Baarke, Andrea; Kliche, Stefanie; Schraven, Burkhart

doi:10.1016/j.molimm.2004.04.009

Cited by 26 publications

(17 citation statements)

References 116 publications

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“…FYB is an adaptor protein participating in TCRtriggered inside-out activation of T cell integrins, and thus, also plays a role in the formation of the IS. It is expressed in many hematopoietic cells with the exception of B cells 21,22 and contains one SH3…”

Section: Identification Of Nck Interaction Partnersmentioning

confidence: 99%

The adapter protein Nck: Role of individual SH3 and SH2 binding modules for protein interactions in T lymphocytes

et al. 2010

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Nck is a ubiquitously expressed, primarily cytosolic adapter protein consisting of one SH2 domain and three SH3 domains. It links receptor and nonreceptor tyrosine kinases to actin cytoskeleton reorganizing proteins. In T lymphocytes, Nck is a crucial component of signaling pathways for T cell activation and effector function. It recruits actin remodeling proteins to T cell receptor (TCR)-associated activation clusters and thereby initiates changes in cell polarity and morphology. Moreover, Nck is crucial for the TCR-induced mobilization of secretory vesicles to the cytotoxic immunological synapse. To identify the interactome of Nck in human T cells, we performed a systematic screen for interaction partners in untreated or pervanadate-treated cells. We used GST fusion proteins containing full length Nck, the combined SH3 domains or the individual SH3 and SH2 domains to precipitate putative Nck interactors from cellular lysates. Protein bands were excised from gels, processed by tryptic in-gel digestion and analyzed by mass spectrometry. Using this approach, we confirmed previously established interactions (e.g., with Slp76, CD3e, WASP, and WIPF1) and identified several novel putative Nck-binding proteins. We subsequently verified the SH2 domain binding to the actin-binding protein HIP55 and to FYB/ADAP, and the SH3-mediated binding to the nuclear proteins SFPQ/NONO. Using laser scanning microscopy, we provide new evidence for a nuclear localization of Nck in human T cells. Our data highlight the fundamental role of Nck in the TCR-to-cytoskeleton crosstalk and point to yet unknown nuclear functions of Nck also in T lymphocytes.

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Section: Identification Of Nck Interaction Partnersmentioning

confidence: 99%

The adapter protein Nck: Role of individual SH3 and SH2 binding modules for protein interactions in T lymphocytes

et al. 2010

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“…It has become clear that effective propagation of intracellular signals is in many systems dependent upon adaptor proteins or molecular scaffolds (9). Such scaffolding proteins do not possess enzymatic activity but rather contain multiple protein docking sites and often lipid interaction motifs, such as PH domains, and function to coordinate formation of signaling complexes (10,11).…”

Section: Ligation Of Cd28 Stimulates the Formation Of A Multimericmentioning

confidence: 99%

Ligation of CD28 Stimulates the Formation of a Multimeric Signaling Complex Involving Grb-2-Associated Binder 2 (Gab2), Src Homology Phosphatase-2, and Phosphatidylinositol 3-Kinase: Evidence That Negative Regulation of CD28 Signaling Requires the Gab2 Pleckstrin Homology Domain

Parry

Whittaker

Sims

et al. 2006

The Journal of Immunology

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Grb-2-associated binder (Gab)2 is a scaffolding adaptor protein that has been reported to promote growth factor and cytokine receptor signal transduction, but inhibit TCR-mediated signaling events. In this study, we show that ligation of CD28 by its natural ligand B7-1/CD80, induces tyrosine phosphorylation of Gab2 and its coassociation with Src homology phosphatase (SHP)-2 and class IA PI3K in Jurkat cells. Overexpression of wild-type Gab2 revealed a negative role in regulation of CD3/CD28 induction of the transcription factors NF-κB and AP-1. To characterize this inhibitory function further, we used Gab2 mutants unable to bind either PI3K or SHP-2 and a PH domain deletion mutant. Although PI3K has previously been implicated as necessary for Gab2-mediated inhibition of TCR signaling, Gab2 mutants defective in their ability to bind PI3K or SHP-2 retained their inhibitory function, whereas deletion of the PH domain ablated the inhibitory effect of Gab2. Together, these data demonstrate that CD28 stimulation of T cells is sufficient to induce an inhibitory multimeric signaling complex involving Gab2, SHP-2, and PI3K. Furthermore, the inhibitory capacity of Gab2 is strictly dependent upon the integrity of its PH domain, suggesting phosphoinositide-mediated membrane recruitment is important to Gab2 function in T cells.

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“…3,24 These findings substantiate the significance of adaptors that mediate cross-talk between different junction types in the testes. Apart from that, other functions are recently uncovered for adaptors, including their participation in cytokine signaling in the testes and immune-related activities 25,26 Based on this emerging evidence, adaptors are proteins with diversified physiological functions in maintaining spermatogenesis, in particular the events of junction restructuring.…”

Section: Nos/no In Junction Dynamicsmentioning

confidence: 99%

Nitric Oxide and Cyclic Nucleotides: Their Roles in Junction Dynamics and Spermatogenesis

Lee

Cheng

2009

Advances in Experimental Medicine and Biology

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Spermatogenesis is a highly complicated process in which functional spermatozoa (haploid, 1n) are generated from primitive mitotic spermatogonia (diploid, 2n). This process involves the differentiation and transformation of several types of germ cells as spermatocytes and spermatids undergo meiosis and differentiation. Due to its sophistication and complexity, testis possesses intrinsic mechanisms to modulate and regulate different stages of germ cell development under the intimate and indirect cooperation with Sertoli and Leydig cells, respectively. Furthermore, developing germ cells must translocate from the basal to the apical (adluminal) compartment of the seminiferous epithelium. Thus, extensive junction restructuring must occur to assist germ cell movement. Within the seminiferous tubules, three principal types of junctions are found namely anchoring junctions, tight junctions, and gap junctions. Other less studied junctions are desmosome-like junctions and hemidesmosome junctions. With these varieties of junction types, testes are using different regulators to monitor junction turnover. Among the uncountable junction modulators, nitric oxide (NO) is a prominent candidate due to its versatility and extensive downstream network. NO is synthesized by nitric oxide synthase (NOS). Three traditional NOS, specified as endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS), and one testis-specific nNOS (TnNOS) are found in the testis. For these, eNOS and iNOS were recently shown to have putative junction regulation properties. More important, these two NOSs likely rely on the downstream soluble guanylyl cyclase/cGMP/protein kinase G signaling pathway to regulate the structural components at the tight junctions and adherens junctions in the testes. Apart from the involvement in junction regulation, NOS/NO also participates in controlling the levels of cytokines and hormones in the testes. On the other hand, NO is playing a unique role in modulating germ cell viability and development, and indirectly acting on some aspects of male infertility and testicular pathological conditions. Thus, NOS/NO bears an irreplaceable role in maintaining the homeostasis of the microenvironment in the seminiferous epithelium via its different downstream signaling pathways.

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The role of adaptor proteins in lymphocyte activation

Cited by 26 publications

References 116 publications

The adapter protein Nck: Role of individual SH3 and SH2 binding modules for protein interactions in T lymphocytes

The adapter protein Nck: Role of individual SH3 and SH2 binding modules for protein interactions in T lymphocytes

Ligation of CD28 Stimulates the Formation of a Multimeric Signaling Complex Involving Grb-2-Associated Binder 2 (Gab2), Src Homology Phosphatase-2, and Phosphatidylinositol 3-Kinase: Evidence That Negative Regulation of CD28 Signaling Requires the Gab2 Pleckstrin Homology Domain

Nitric Oxide and Cyclic Nucleotides: Their Roles in Junction Dynamics and Spermatogenesis

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