Vav1-mediated Scaffolding Interactions Stabilize SLP-76 Microclusters and Contribute to Antigen-dependent T Cell Responses

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2011 Mar 10

PMID 21386095

Citations 24

Authors

Nicholas R Sylvain

Ken Nguyen

Stephen C Bunnell

Affiliations

Soon will be listed here.

Abstract

The guanine nucleotide exchange factor (GEF) Vav1 synergizes with the adaptor protein SLP-76 (Src homology 2 domain--containing leukocyte phosphoprotein of 76 kD) to support T cell development and activation. In response to ligation of the T cell receptor (TCR), SLP-76 is assembled into microclusters that provide an essential platform for the signaling events that drive T cell activation. We found that Vav1 selectively entered SLP-76 microclusters, rather than TCR microclusters, influencing their stability and function. The carboxyl terminus of Vav1, which consists of Src homology domains, was both necessary and sufficient for the entry of Vav1 into SLP-76 microclusters; however, this fragment of Vav1 was insufficient to stabilize the microclusters, and it potently suppressed T cell activation. This indicated that the amino terminus of Vav1, which has the GEF domain, also contributed to the integrity of SLP-76 microclusters and thereby to T cell activation. These microcluster-stabilizing functions were independent of the GEF activity in the amino terminus of Vav1 and were unaffected if the GEF function of Vav1 was either inactivated or constitutively activated by mutation. In contrast, Vav1 deletion mutants lacking either the calponin homology domain or the catalytic core of the GEF exhibited mild scaffolding defects, but they differentially affected TCR-dependent calcium ion (Ca²+) responses. We conclude that multiple GEF-independent scaffolding functions distributed throughout the amino terminus of Vav1 contribute to the activation of T cells by acting synergistically to increase the stability and function of SLP-76 microclusters.

Citing Articles

The Multiple Roles of the Cytosolic Adapter Proteins ADAP, SKAP1 and SKAP2 for TCR/CD3 -Mediated Signaling Events.

Dadwal N, Mix C, Reinhold A, Witte A, Freund C, Schraven B Front Immunol. 2021; 12:703534.

PMID: 34295339 PMC: 8290198. DOI: 10.3389/fimmu.2021.703534.

LFA-1 and kindlin-3 enable the collaborative transport of SLP-76 microclusters by myosin and dynein motors.

Eidell K, Lovy A, Sylvain N, Scangarello F, Muendlein H, Ophir M J Cell Sci. 2021; 134(16).

PMID: 34279667 PMC: 8435290. DOI: 10.1242/jcs.258602.

Vav2 lacks Ca entry-promoting scaffolding functions unique to Vav1 and inhibits T cell activation via Cdc42.

Fray M, Charpentier J, Sylvain N, Seminario M, Bunnell S J Cell Sci. 2020; 133(5).

PMID: 31974114 PMC: 7075049. DOI: 10.1242/jcs.238337.

The Vav GEF Family: An Evolutionary and Functional Perspective.

Rodriguez-Fdez S, Bustelo X Cells. 2019; 8(5).

PMID: 31100928 PMC: 6562523. DOI: 10.3390/cells8050465.

ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters.

Lewis J, Scangarello F, Murphy J, Eidell K, Sodipo M, Ophir M J Cell Sci. 2018; 131(21).

PMID: 30305305 PMC: 6240300. DOI: 10.1242/jcs.215517.

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