WASp Family Verprolin-homologous Protein-2 (WAVE2) and Wiskott-Aldrich Syndrome Protein (WASp) Engage in Distinct Downstream Signaling Interactions at the T Cell Antigen Receptor Site

Pauker, Maor H.; Reicher, Barak; Joseph, Noah; Wortzel, Inbal; Jakubowicz, Shlomi; Noy, Elad; Perl, Orly; Barda‐Saad, Mira

doi:10.1074/jbc.m114.591685

Cited by 24 publications

(35 citation statements)

References 58 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To this end, the YFP-WAVE2-CFP plasmid contains silent mutations that render it resistant to the siRNA used (see Methods). As was previously shown by us, WAVE2 knockdown disrupts the activation of LFA-1, as demonstrated using KIM127, an antibody specific to the activated conformation of LFA-115. Here, we show that YFP-WAVE2-CFP expression rescues LFA-1 activation in WAVE2 knockdown cells, demonstrating the normal functionality of YFP-WAVE2-CFP (see Supplementary Fig.…”

Section: Resultssupporting

confidence: 87%

“…We recently demonstrated that WAVE2 is recruited to the TCR site and co-localizes with the nucleation promoting factor (NPF), WASp, during the initiation of T-cell activation15. Previously, we showed that following recruitment to TCR-based clusters, WASp undergoes ubiquitylation-dependent degradation34.…”

Section: Resultsmentioning

confidence: 99%

“…S10a). Furthermore, we determined the cellular distribution of YFP-WAVE2-CFP in comparison to the previously described YFP-WAVE2 protein15 (see Supplementary Fig. S10b).…”

Section: Resultsmentioning

confidence: 99%

“…It was shown that WAVE2 is recruited to the IS, and that RNAi-mediated depletion of WAVE2 inhibits TCR-induced spreading and F-actin polymerization at the IS1213. WAVE2 was also found to be involved in integrin-mediated TCR-stimulated adhesion1415, Ca 2+ release-activated Ca 2+ (CRAC) channels-mediated Ca 2+ entry, TCR-mediated activation of nuclear factor of activated T cells (NFAT), and is required for TCR-stimulated IL-2 promoter activity121416. These early observations established WAVE2 as an integral component of TCR signaling cascade.…”

mentioning

confidence: 99%

See 3 more Smart Citations

A conformational change within the WAVE2 complex regulates its degradation following cellular activation

Joseph

Biber

Fried

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

WASp family Verprolin-homologous protein-2 (WAVE2), a member of the Wiskott-Aldrich syndrome protein (WASp) family of actin nucleation promoting factors, is a central regulator of actin cytoskeleton polymerization and dynamics. Multiple signaling pathways operate via WAVE2 to promote the actin-nucleating activity of the actin-related protein 2/3 (Arp2/3) complex. WAVE2 exists as a part of a pentameric protein complex known as the WAVE regulatory complex (WRC), which is unstable in the absence of its individual proteins. While the involvement of WAVE2 in actin polymerization has been well documented, its negative regulation mechanism is poorly characterized to date. Here, we demonstrate that WAVE2 undergoes ubiquitylation in a T-cell activation dependent manner, followed by proteasomal degradation. The WAVE2 ubiquitylation site was mapped to lysine 45, located at the N-terminus where WAVE2 binds to the WRC. Using Förster resonance energy transfer (FRET), we reveal that the autoinhibitory conformation of the WRC maintains the stability of WAVE2 in resting cells; the release of autoinhibition following T-cell activation facilitates the exposure of WAVE2 to ubiquitylation, leading to its degradation. The dynamic conformational structures of WAVE2 during cellular activation dictate its degradation.

show abstract

Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

“…S10a). Furthermore, we determined the cellular distribution of YFP-WAVE2-CFP in comparison to the previously described YFP-WAVE2 protein15 (see Supplementary Fig. S10b).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

A conformational change within the WAVE2 complex regulates its degradation following cellular activation

Joseph

Biber

Fried

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast, LAT-dependent SLP-76 clusters have a direct role in activating the Arp2/3 complex and actin polymerization. After TCR engagement, WASp and WAVE2 are rapidly recruited to the LAT signaling complex (14, 58), although they disassociate to form separate structures after longer stimulation times (14). The association of WASp, WAVE2, and SLP-76 with LAT may be important for coordinating the correct spatial context to initiate the actin polymerization necessary for dSMAC and pSMAC formation.…”

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

Lymphocyte mechanotransduction: The regulatory role of cytoskeletal dynamics in signaling cascades and effector functions

Ben‐Shmuel¹,

Joseph²,

Sabag³

et al. 2019

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

The process of mechanotransduction, that is, conversion of physical forces into biochemical signaling cascades, has attracted interest as a potential mechanism for regulating immune cell activation. The cytoskeleton serves a critical role in a variety of lymphocyte functions, from cellular activation, proliferation, adhesion, and migration, to creation of stable immune synapses, and execution of functions such as directed cytotoxicity. Though traditionally considered a scaffold that enables formation of signaling complexes that maintain stable immune synapses, the cytoskeleton was additionally shown to play a dynamic role in lymphocyte signaling cascades by sensing physical cues such as substrate rigidity, and transducing these mechanical features into chemical signals that ultimately influence lymphocyte effector functions. It is thus becoming clear that cytoskeletal dynamics are essential for the lymphocyte response, beyond the role of the cytoskeleton as a stationary framework. Here, we describe the transduction of extracellular forces to activate signaling pathways and effector functions mediated through the cytoskeleton in lymphocytes. We also highlight recent discoveries of cytoskeleton‐mediated mechanotransduction on intracellular signaling pathways in NK cells.

show abstract

WASp Family Verprolin-homologous Protein-2 (WAVE2) and Wiskott-Aldrich Syndrome Protein (WASp) Engage in Distinct Downstream Signaling Interactions at the T Cell Antigen Receptor Site

Cited by 24 publications

References 58 publications

A conformational change within the WAVE2 complex regulates its degradation following cellular activation

A conformational change within the WAVE2 complex regulates its degradation following cellular activation

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

Lymphocyte mechanotransduction: The regulatory role of cytoskeletal dynamics in signaling cascades and effector functions

Contact Info

Product

Resources

About