Specific tyrosine phosphorylation sites on cortactin regulate Nck1-dependent actin polymerization in invadopodia

Oser, Matthew G.; Mader, Christopher C.; Gil-Henn, Hava; Magalhaes, Marco; Bravo‐Cordero, Jose Javier; Koleske, Anthony J.; Condeelis, John S.

doi:10.1242/jcs.068163

Cited by 141 publications

(189 citation statements)

References 34 publications

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“…Moreover, the HS1 homologue cortactin was shown to recruit Nck to invadopodia in breast carcinoma cells. The phosphorylation of cortactin Y 421 and Y 466 was prerequisite for the recruitment of Nck and the induction of actin polymerization in invadopodia, thus facilitating matrixproteolysis-dependent tumor cell invasion [45]. Taken together, our data show that Nck and HS1 physically interact upon CXCR4 ligation and facilitate SDF1α-induced T-cell migration by regulating actin polymerization.…”

Section: Discussionmentioning

confidence: 62%

SDF1α‐induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells

2014

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Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptorassociated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration.Keywords: CXCR4 r HS1 r Nck r SDF1α r T cells IntroductionT cells govern adaptive immunity by cytokine secretion or cytotoxic effector function. After development in the thymus, naive T lymphocytes constantly recirculate between the blood stream and lymphoid tissues. At the molecular level, this homing and migration processes rely on complex interactions of selected chemokines with their receptors on respective T cells and of T-cell adhesion molecules binding to their ligands on endothelial cells or the extracellular matrix. Individual interactions elicit specific signaling pathways that induce dynamic cytoskeletal rearrangements, which enable lymphocytes to adhere to or pass a certain substrate or to transmigrate through a given endothelium. Morphologically, circular floating T cells adopt a migratory phenotype characterized Correspondence: Dr. Marcus Lettau e-mail: lettau@immunologie.uni-kiel.de by a leading edge at the front and an uropod at the rear. When T cells encounter their antigen on an antigen-presenting cell in the lymph nodes or spleen, migration is halted and the cells rapidly polarize toward the intercellular contact area. The subsequent formation of the so-called immunological synapse (IS) is again accompanied by complex cytoskeletal changes and comprises the structural basis for T-cell activation. This primary antigenic stimulation ultimately results in cell-cycle progression, clonal expansion, and differentiation to T-effector cells. The activated T cells regain migratory potential, leave the lymphoid tissue, and search the periphery for infected or transformed cells displaying their cognate antigen. Upon antigen encounter, the T cells adhere to their target cell and polarize toward the intercell...

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Section: Discussionmentioning

confidence: 62%

SDF1α‐induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells

2014

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“…All three cortactin variants have wild type affinity for actin filaments (33). Published experiments with these mutated proteins showed that these reciprocal interactions between Arg and cortactin contribute to cell edge protrusion in motile cells and stabilize the dendritic spines of neurons (7,15,34).…”

Section: Resultsmentioning

confidence: 99%

Abl2/Abl-related Gene Stabilizes Actin Filaments, Stimulates Actin Branching by Actin-related Protein 2/3 Complex, and Promotes Actin Filament Severing by Cofilin

Courtemanche

Gifford

Simpson

et al. 2015

Journal of Biological Chemistry

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Background: Arg/Abl2 has two actin-binding domains, but how they influence actin filaments was unknown. Results: Arg and cortactin cooperatively stabilize actin filaments; Arg enhances Arp2/3 complex activation and stimulates severing by cofilin. Conclusion: Arg directly regulates actin filament stability, branching, and severing, which are modulated by cortactin. Significance: These activities may underlie the control of actin-based cellular structures by Arg.

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“…Fifty thousand UMSCC47 cells were plated on Alexa Fluor-488 gelatin matrix-coated Mattek dishes (10 mm) and incubated for 24 hours as described previously (23,24). Where indicated, 50,000 (1:1) or 200,000 (4:1) neutrophils were added to the culture.…”

Section: Matrix Degradation and Invadopodia Analysismentioning

confidence: 99%

Neutrophils Increase Oral Squamous Cell Carcinoma Invasion through an Invadopodia-Dependent Pathway

Glogauer

Sun

Bradley

et al. 2015

Cancer Immunology Research

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Neutrophils have recently been shown to promote invasion and correlate with a poor prognosis in different cancers, including head and neck squamous cell carcinomas. In this study, we analyze the effects of neutrophils in the invasion of oral squamous cell carcinoma (OSCC) using a combination of conditioned media, direct and indirect coculture of human peripheral blood neutrophils, and UMSCC47 cells (OSCC cell line). Invasion and matrix degradation were determined using a modified in vitro invasion assay and an invadopodia assay, respectively. UMSCC47 and neutrophil cocultures or conditioned media from cocultures increased UMSCC47 invasion, invadopodia formation, and matrix degradation. Further analysis revealed an increase in TNFa and IL8 in supernatants of cocultures compared with neutrophil or UMSCC47 cultures alone and that inhibition of TNFa and IL8 significantly decreased OSCC invasion. Our results show that neutrophils increase the invasiveness of OSCC through the activation of invadopodia and matrix degradation, suggesting a paracrine activation loop between the two cells. Importantly, the presence of neutrophils in the oral environment may modulate the clinical behavior of OSCC.

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Specific tyrosine phosphorylation sites on cortactin regulate Nck1-dependent actin polymerization in invadopodia

Cited by 141 publications

References 34 publications

SDF1α‐induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells

SDF1α‐induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells

Abl2/Abl-related Gene Stabilizes Actin Filaments, Stimulates Actin Branching by Actin-related Protein 2/3 Complex, and Promotes Actin Filament Severing by Cofilin

Neutrophils Increase Oral Squamous Cell Carcinoma Invasion through an Invadopodia-Dependent Pathway

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