Nck adapter proteins: functional versatility in T cells

Lettau, Marcus; Pieper, Jennifer; Janßen, Ottmar

doi:10.1186/1478-811x-7-1

Cited by 98 publications

(116 citation statements)

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“…Moreover, a detailed analysis revealed that Nck specifically binds to phosphorylated Y 378 of HS1 via its SH2 domain. Nck1 and Nck2 display 68% identity at the amino acid level and are regarded to be functionally redundant in many aspects although some Nck1-or Nck2-specific interactions/functions have been reported (reviewed in [2]). Nonetheless, binding specificities of the isolated SH2 domains of Nck1 and Nck2 are nearly the same and both recognize a YDEV consensus-binding sequence [35].…”

Section: Discussionmentioning

confidence: 99%

“…Nck1 and Nck2 display 68% identity at the amino acid level and are regarded to be functionally redundant in many aspects [2,5]. We therefore analyzed, whether HS1 would also associate with the SH2 domain of Nck2.…”

Section: Nck Interacts With Hs1mentioning

confidence: 99%

“…We detected a major band at about 80 kDa only after precipitation of HS1 from stimulated cells and not in the respective controls. By stripping and reprobing the blot with an HS1-specific antibody we clearly assigned this band to HS1.Nck1 and Nck2 display 68% identity at the amino acid level and are regarded to be functionally redundant in many aspects [2,5]. We therefore analyzed, whether HS1 would also associate with the SH2 domain of Nck2.…”

mentioning

confidence: 99%

“…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].…”

mentioning

confidence: 99%

“…Functionally, Nck links SH2 domainbinding receptors and receptor-associated phosphoproteins with SH3 domain-interacting proteins that directly or indirectly affect the actin cytoskeleton. Nck was functionally associated with a plethora of receptor-initiated signaling processes including tissue development and homeostasis, malignant transformation, and invasiveness of tumor cells and the activation and effector function of immune cells (reviewed in [2,6]). …”

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confidence: 99%

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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: 99%

Section: Nck Interacts With Hs1mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

2014

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CRK and NCK adaptors may functionally overlap in zebrafish neurodevelopment, as indicated by common binding partners and overlapping expression patterns

Stergas,

Dillon‐Martin,

Dumas

et al. 2023

FEBS Letters

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CRK adaptor proteins are important for signal transduction mechanisms driving cell proliferation and positioning during vertebrate central nervous system development. Zebrafish lacking both CRK family members exhibit small, disorganized retinas with 50% penetrance. The goal of this study was to determine whether another adaptor protein might functionally compensate for the loss of CRK adaptors. Expression patterns in developing zebrafish, and bioinformatic analyses of the motifs recognized by their SH2 and SH3 domains, suggest NCK adaptors are well‐positioned to compensate for loss of CRK adaptors. In support of this hypothesis, proteomic analyses found CRK and NCK adaptors share overlapping interacting partners including known regulators of cell adhesion and migration, suggesting their functional intersection in neurodevelopment.

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Mechanism of Bile Acid in Regulating Platelet Function and Thrombotic Diseases

Zhou,

Zhang

et al. 2024

Advanced Science

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Platelets play a key role in physiological hemostasis and pathological thrombosis. Based on the limitations of current antiplatelet drugs, it's important to elucidate the mechanisms of regulating platelet activation. In addition to dissolving lipid nutrients, bile acids (BAs) can regulate platelet function. However, the specific mechanisms underlying BAs‐mediated effects on platelet activation and thrombotic diseases remain unknown. Therefore, the effects of BAs on platelets and intracellular regulatory mechanisms are explored. It is showed that the inhibitory effect of secondary BAs is more significant than that of primary BAs; lithocholic acid (LCA) shows the highest inhibitory effect. In the process of platelet activation, BAs suppress platelet activation via the spleen tyrosine kinase (SYK), protein kinase B (Akt), and extracellular signal‐regulated kinase1/2 (Erk1/2) pathways. Nck adaptor proteins (NCK1) deficiency significantly suppress the activity of platelets and arterial thrombosis. Phosphorylated proteomics reveal that LCA inhibited phosphorylation of syntaxin‐11 at S80/81 in platelets. Additional LCA supplementation attenuated atherosclerotic plaque development and reduced the inflammation in mice. In conclusion, BAs play key roles in platelet activation via Syk, Akt, ERK1/2, and syntaxin‐11 pathways, which are associated with NCK1. The anti‐platelet effects of BAs provide a theoretical basis for the prevention and therapy of thrombotic diseases.

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Nck adapter proteins: functional versatility in T cells

Cited by 98 publications

References 146 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

CRK and NCK adaptors may functionally overlap in zebrafish neurodevelopment, as indicated by common binding partners and overlapping expression patterns

Mechanism of Bile Acid in Regulating Platelet Function and Thrombotic Diseases

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