Actin cytoskeletal dynamics in T lymphocyte activation and migration

Samstag, Yvonne; Eibert, Sybille M.; Klemke, Martin; Wabnitz, Guido H.

doi:10.1189/jlb.0602272

Cited by 155 publications

(155 citation statements)

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“…The well characterized maturation steps of ␣␤ T cells in the thymus are also governed by trafficking events and positional cues driven by guidance molecules, including chemokines, adhesion molecules, and extracellular matrix components (3)(4)(5)(6). Rearrangement of the actin cytoskeleton is regulated during both T cell receptor signaling and T cell migration (7)(8)(9), but much less is known about its requirement during T cell development. The small Rho-family GTPases and their guanine nucleotide exchange factors (GEFs), proteins known to regulate the actin cytoskeleton, are clearly required during thymocyte development (10)(11)(12).…”

mentioning

confidence: 99%

Wiskott–Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development

Cotta-de-Almeida

Westerberg

Maillard

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

100

120

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cytoskeleton ͉ thymus ͉ migration ͉ colitis ͉ knockout mice L ymphoid progenitors enter the thymus to initiate a complex differentiation process resulting in maturation of T cells (1, 2). The well characterized maturation steps of ␣␤ T cells in the thymus are also governed by trafficking events and positional cues driven by guidance molecules, including chemokines, adhesion molecules, and extracellular matrix components (3-6). Rearrangement of the actin cytoskeleton is regulated during both T cell receptor signaling and T cell migration (7-9), but much less is known about its requirement during T cell development. The small Rho-family GTPases and their guanine nucleotide exchange factors (GEFs), proteins known to regulate the actin cytoskeleton, are clearly required during thymocyte development (10-12). Although these molecules are also known to regulate cell adhesion and migration, their involvement in thymocyte trafficking has not been thoroughly assessed. The small GTPase effector molecule Wiskott-Aldrich syndrome protein (WASP) has also been demonstrated to be a critical regulator of antigen receptor signaling, actin cytoskeletal rearrangements, and lymphocyte migration (13-22). Although WASP deficiency has been correlated with lower numbers of naïve T cells (23), WASP does not seem to play a critical role in T cell development. Moreover, despite a large body of evidence showing a role for WASP in T cell signaling, its role in thymocyte migration has not been studied. WASP belongs to the WASP family of proteins, including WASP, N-WASP, and WAVE/SCAR molecules 1-3 (24). In particular, N-WASP, which shares 50% homology with WASP, may serve specific and redundant function with WASP in hematopoietic cells. In fact, we have shown that expression of N-WASP in WASP-deficient T cells partly restores CD3-mediated proliferation, implying that WASP and N-WASP might share functions in T cells (25).Here we sought to explore the importance of cytoskeletal regulation for thymocyte development by examining the unique and redundant roles of WASP and N-WASP. Using two complementary approaches, we analyzed T cells devoid of WASP and N-WASP and demonstrated that thymopoiesis cannot proceed in the absence of WASP and N-WASP. Results Deletion of WASP and N-WASP in Lymphocytes Using the RAG-2-Deficient Complementation System Leads to a Block in T Cell Development.We have demonstrated that lymphoid development is normal in WASP knockout (WKO) mice (20). We hypothesized that N-WASP might have some overlapping functions with WASP during lymphopoiesis and sought to investigate the unique and redundant activities for WASP and N-WASP in T cell development and function. To circumvent the embryonic lethality of N-WASP germ-line inactivation in mice (26), we used the RAG2-deficient blastocyst complementation system (27). Blastocysts from RAG-2-deficient mice implanted into foster mothers generate animals that fail to rearrange antigen receptor genes and consequently lack mature B and T cells. Injection of gene-targeted ES cells into RAG-2-...

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mentioning

confidence: 99%

Wiskott–Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development

Cotta-de-Almeida

Westerberg

Maillard

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

100

120

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“…13 Changes in the actin cytoskeleton are accomplished by a variety of actin-binding proteins such as cofilin, a-actinin, filamin and plastin. 14 Three highly homologous plastin isoforms have been identified in humans 15 : the isoform L-plastin is expressed in cells of the hematopoietic cell lineage, T-plastin is constitutively expressed in epithelial and mesenchymal cells and I-plastin is specifically expressed in the intestinal and renal brush border microvilli. 16 The hematopoetic isoform L-plastin contains 2 calcium-binding sites, a potential calmodulin binding site and 2 tandem actin-binding domains.…”

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confidence: 99%

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

Klemke

Rafael

Wabnitz

et al. 2007

Intl Journal of Cancer

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The leukocyte specific actin-binding protein L-plastin is aberrantly expressed in several nonhematopoetic malignant tumors. However, little is known about the functional consequences of Lplastin expression. Here, we investigated the function of L-plastin in human malignant melanoma cells. Knock-down of endogenous L-plastin by siRNA treatment reduced migration of the melanoma cell line IF6. However, in melanoma patients, no correlation existed between L-plastin expression and tumor stages. This implied that additional factors such as phosphorylation of L-plastin may influence its function in tumor cells. To investigate this further, EGFP-tagged wild-type L-plastin (wt-LPL-EGFP) and a mutated, nonphosphorylatable L-plastin protein (5A7A-LPL-EGFP), were expressed in the L-plastin negative melanoma cell line MV3. Biochemical analysis revealed that wt-LPL-EGFP is phosphorylated in MV3 cells while 5A7A-LPL-EGFP is not. Although both wt-LPL-EGFP and 5A7A-LPL-EGFP were targeted to, and promote the formation of, vinculin-containing adhesion sites, static adhesion to either Matrigel or isolated extracellular matrix molecules was neither influenced by expression of wt-LPL-EGFP nor by expression of 5A7A-LPL-EGFP when compared with EGFP expressing control cells. In contrast, haptotactic, but not chemotactic, migration of melanoma cells towards either Matrigel or isolated extracellular matrix molecules was similarly enhanced, if either 5A7A-LPL-EGFP or wt-LPL-EGFP were expressed in MV3 cells. Interestingly, only cells expressing the phosphorylatable wt-LPL-EGFP protein showed enhanced invasion into Matrigel. In line with these findings the in vivo metastatic capacity of mouse B16 melanoma cells correlates with expression and phosphorylation of L-plastin. These data show that an increase in melanoma cell invasiveness requires not only expression but also phosphorylation of L-plastin. ' 2007 Wiley-Liss, Inc.Key words: migration; invasion; adhesion; L-plastin; melanoma Malignant melanoma is a very aggressive type of cancer that frequently metastasizes to distant organs. The capacity of tumor cells to form metastatic foci correlates with the ability to proteolytically degrade basement membrane barriers and to adhere to and migrate through extracellular matrix layers. 1,2 Two classes of molecules are mainly involved in these processes: the matrix metalloproteinases (MMPs) 3 and integrins. 4,5 Integrins are a large family of adhesion receptors involved in cell-cell and cellextracellular matrix interactions. They consist of heterodimers of 2 noncovalently associated a-and b-subunits. 6 The role of integrins in tumor cell metastasis has been intensively studied. 4,5,7 In human melanoma, especially b1-and b3-subunit containing integrins play important roles in metastasis, through an enhancement of adhesion, migration and invasion. 8,9 Moreover, the cell surface expression levels of many integrins can be directly correlated with the metastatic potential of melanoma cells. [10][11][12] Modulation of the actin cytoskeleton is critical f...

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“…Since all these processes crucially depend on dynamic changes of the lymphocyte cytoskeleton, the engagement of T-cell surface receptors (including the TCR, chemokine receptors, and integrins) activates multiple actin-regulatory proteins that work in concert to adjust actin polymerization. This regulatory network also includes the adapter proteins Nck and HS1 (reviewed in [1][2][3][4]). The Nck (noncatalytic region of tyrosine kinase) family of adapter proteins comprises two members (Nck1/Nckα and Nck2/Nckβ, also termed Grb4) that are structurally and functionally redundant in many aspects [5].…”

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confidence: 99%

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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Actin cytoskeletal dynamics in T lymphocyte activation and migration

Cited by 155 publications

References 261 publications

Wiskott–Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development

Wiskott–Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development

Phosphorylation of ectopically expressed L‐plastin enhances invasiveness of human melanoma cells

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

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