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Nck adapter proteins: functional versatility in T cells

By Marcus Lettau, Jennifer Pieper and Ottmar Janssen


Nck is a ubiquitously expressed adapter protein that is almost exclusively built of one SH2 domain and three SH3 domains. The two isoproteins of Nck are functionally redundant in many aspects and differ in only few amino acids that are mostly located in the linker regions between the interaction modules. Nck proteins connect receptor and non-receptor tyrosine kinases to the machinery of actin reorganisation. Thereby, Nck regulates activation-dependent processes during cell polarisation and migration and plays a crucial role in the signal transduction of a variety of receptors including for instance PDGF-, HGF-, VEGF- and Ephrin receptors. In most cases, the SH2 domain mediates binding to the phosphorylated receptor or associated phosphoproteins, while SH3 domain interactions lead to the formation of larger protein complexes. In T lymphocytes, Nck plays a pivotal role in the T cell receptor (TCR)-induced reorganisation of the actin cytoskeleton and the formation of the immunological synapse. However, in this context, two different mechanisms and adapter complexes are discussed. In the first scenario, dependent on an activation-induced conformational change in the CD3ε subunits, a direct binding of Nck to components of the TCR/CD3 complex was shown. In the second scenario, Nck is recruited to the TCR complex via phosphorylated Slp76, another central constituent of the membrane proximal activation complex. Over the past years, a large number of putative Nck interactors have been identified in different cellular systems that point to diverse additional functions of the adapter protein, e.g. in the control of gene expression and proliferation

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Publisher: BioMed Central
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  1. A casein kinase I activity is constitutively associated with Nck.
  2. (2008). A conformational change senses the strength of T cell receptor-ligand interaction during thymic selection. Proc Natl Acad Sci USA 2006, 103:9625–9630. 5 5 . T a i l o rP ,T s a iS ,S h a m e l iA ,S e r r aP ,W a n gJ ,R o b b i n sS ,N a g a t aM
  3. A GTPase-independent mechanism of p21-activated kinase activation. Regulation by sphingosine and other biologically active lipids. JB i o lC h e m1998,
  4. (1998). A Nck-Pak1 signaling module is required for T-cell receptor-mediated activation of NFAT, but not of JNK.
  5. A neural WiskottAldrich Syndrome protein-mediated pathway for localized activation of actin polymerization that is regulated by cortactin.
  6. (1999). a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling.
  7. (1995). A novel ligand for SH3 domains. The Nck adaptor protein binds to a serine/threonine kinase via an SH3 domain.
  8. (1998). A novel regulator of p21-activated kinases.
  9. (1999). A tyrosine-phosphorylated protein that binds to an important regulatory region on the cool family of p21-activated kinase-binding proteins. JB i o lC h e m
  10. (1994). Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. Genes Dev
  11. (1999). Actin-based motility of vaccinia virus mimics receptor tyrosine kinase signalling. Nature
  12. (2006). Activation of the nonreceptor protein tyrosine kinase Ack by multiple extracellular stimuli. Proc Natl Acad Sci USA
  13. (2007). Adang LA and Macara IG: Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7. Cell
  14. (1999). Alarcon B and Alcover A: The CD3 epsilon subunit of the TCR contains endocytosis signals.
  15. (2003). All roads lead to actin: the intimate relationship between TCR signaling and the cytoskeleton. Immunol Rev
  16. (1997). An o v e ll i g a n d for an SH3 domain of the adaptor protein Nck bears an SH2 domain and nuclear signaling motifs. Biochem Biophys Res Commun
  17. (1995). and Cerione RA: Identification of a mouse p21Cdc42/Rac activated kinase.
  18. (2004). and Hooghe-Peters EL: The suppressor of cytokine signaling (SOCS)-7 interacts with the actin cytoskeleton through vinexin. Exp Cell Res
  19. (2004). Appella E and Samelson LE: Binding specificity of multiprotein signaling complexes is determined by both cooperative interactions and affinity preferences. Biochemistry
  20. (1999). Association of Nck with tyrosine-phosphorylated SLP-76 in activated T lymphocytes.
  21. (1995). Binding of NCK to SOS and activation of ras-dependent gene expression. M o lC e l lB i o l
  22. (2003). Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation. Nat Cell Biol
  23. (2003). Biology of the p21-activated kinases. Annu Rev Biochem
  24. (2008). Carrizosa E and Shaffer MH: The actin cytoskeleton in T cell activation. Annu Rev Immunol
  25. (2000). Characterization of Ggrb4, an adapter protein interacting with Bcr-Abl. Blood
  26. (2001). complex is activated by the T-cell receptor independent of Nck,
  27. (2006). Cytotoxic T lymphocytes kill multiple targets simultaneously via spatiotemporal uncoupling of lytic and stimulatory synapses. Proc Natl Acad Sci USA
  28. (2003). Disease-causing SAP mutants are defective in ligand binding and protein folding. Biochemistry
  29. (2000). Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling. Mol Cell Biol
  30. (2005). Dynamic molecular interactions linking the T cell antigen receptor to the actin cytoskeleton. Nat Immunol
  31. (2005). Dynamic recruitment of PAK1 to the immunological synapse is mediated by PIX independently of SLP-76 and Vav1. Nat Immunol
  32. Ek-Rylander B and Ruoslahti E: R-Ras contains a proline-rich site that binds to SH3 domains and is required for integrin activation by R-Ras.
  33. (2001). Enteropathogenic E. coli Tir binds Nck to initiate actin pedestal formation in host cells.
  34. (2004). EphB1-mediated cell migration requires the phosphorylation of paxillin at
  35. (1999). Farago A and Buday L: Characterization of interactions of Nck with Sos and dynamin. Cell Signal
  36. (1997). Fibronectin-stimulated signaling from a focal adhesion kinase-c-Src complex: involvement of the Grb2, p130cas, and Nck adaptor proteins. Mol Cell Biol
  37. (2007). Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity
  38. (2003). Gertler FB and Pawson T: The murine Nck SH2/SH3 adaptors are important for the development of mesoderm-derived embryonic structures and for regulating the cellular actin network. Mol Cell Biol
  39. (1996). Hepatocyte growth factor induces activation of Nck and phospholipase C-gamma in lung carcinoma cells. Cancer Lett
  40. (2000). Identification and characterization of a new family of guanine nucleotide exchange factors for the ras-related GTPase Ral.
  41. (2001). Identification and kinetic analysis of the interaction between
  42. (2006). Immune regulation by SLAM family receptors and SAP-related adaptors. Nat Rev Immunol
  43. (2005). Immunological synapses are versatile structures enabling selective T cell polarization. Immunity
  44. Independent SH2-binding sites mediate interaction of Dok-related protein with RasGTPase-activating protein and Nck.
  45. (2000). Interaction between PAK and nck: a template for Nck targets and role of PAK autophosphorylation. Mol Cell Biol
  46. (1999). Interaction of insulin receptor substrate 3 with insulin receptor, insulin receptor-related receptor, insulin-like growth factor-1 receptor, and downstream signaling proteins.
  47. (1996). Interactions between Src homology (SH) 2/SH3 adapter proteins and the guanylnucleotide exchange factor SOS are differentially regulated by insulin and epidermal growth factor.
  48. (2004). Involvement of the Wiskott-Aldrich syndrome protein and other actin regulatory adaptors in T cell activation. Semin Immunol
  49. Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signaling.
  50. (2001). Isolation of hNap1BP which interacts with human Nap1 (NCKAP1) whose expression is down-regulated in Alzheimer's disease. Gene
  51. (2003). KT and Howell BW: Nck beta interacts with tyrosine-phosphorylated disabled 1 and redistributes in Reelin-stimulated neurons. Mol Cell Biol
  52. (1998). Leung T and Lim L: PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol Cell
  53. (2005). Ligand-induced conformational change in the T-cell receptor associated with productive immune synapses. Blood
  54. (2002). Lymphocyte-mediated cytotoxicity. Annu Rev Immunol
  55. (1994). Marcilla A and Robbins KC: Physical association between Src homology 3 elements and the protein product of the c-cbl proto-oncogene. JB i o lC h e m
  56. (1998). Membrane targeting of p21-activated kinase 1 (PAK1) induces neurite outgrowth from PC12 cells.
  57. Modulation of protein translation by
  58. (1996). Molecular cloning of p125Nap1, a protein that associates with an SH3 domain of Nck. Biochem Biophys Res Commun
  59. (2001). Multiple interactions of the cytosolic polyproline region of the CD95 ligand: hints for the reverse signal transduction capacity of a death factor. FEBS Lett
  60. (2006). Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes.
  61. Nck and phosphatidylinositol 4,5-bisphosphate synergistically activate actin polymerization through the N-WASP-Arp2/3 pathway.
  62. (2006). Nck in a complex containing the catalytic subunit of protein phosphatase 1 regulates eukaryotic initiation factor 2alpha signaling and cell survival to endoplasmic reticulum stress.
  63. Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase.
  64. (2004). Nck-1 antagonizes the endoplasmic reticulum stress-induced inhibition of translation.
  65. (2008). Nck-1 interacts with PKR and modulates its activation by dsRNA. Biochem Biophys Res Commun
  66. (2002). Nck-2 interacts with focal adhesion kinase and modulates cell motility.
  67. (1998). Nck-2, a novel Src homology2/3-containing adaptor protein that interacts with the LIM-only protein PINCH and components of growth factor receptor kinase-signaling pathways. Mol Biol Cell
  68. (2001). Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton. Oncogene
  69. (2007). Nck1 selectively modulates eIF2alphaSer51 phosphorylation by a subset of eIF2alpha-kinases.
  70. (2007). Nckbeta adapter controls neuritogenesis by maintaining the cellular paxillin level. Mol Cell Biol
  71. (2000). Nckbeta adapter regulates actin polymerization in NIH 3T3 fibroblasts in response to platelet-derived growth factor bb. Mol Cell Biol
  72. Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. JC l i nI n v e s t2006,
  73. (1997). NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain.
  74. (1990). Novel post-translational regulation of TCR expression in CD4+CD8+ thymocytes influenced by CD4. Nature
  75. (2003). NS: T-cell receptor signal transmission: who gives an ITAM?. Trends Immunol
  76. (2001). Paxillin-ARF GAP signaling and the cytoskeleton. Curr Opin Cell Biol
  77. Phosphorylation of Nck in response to a variety of receptors, phorbol myristate acetate, and cyclic AMP. M o lC e l lB i o l1992,
  78. (2006). Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of Nck and activation of Fyn leading to SAPK2/p38 activation and endothelial cell migration in response to VEGF.
  79. (2003). Positive and negative regulation of Tcell activation through kinases and phosphatases.
  80. (1999). Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation. Curr Biol
  81. (2002). Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell
  82. (1998). Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity
  83. (1993). Regulation of T cell receptor expression in immature CD4+CD8+ thymocytes by p56lck tyrosine kinase: basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules.
  84. (1999). Requirement of multiple SH3 domains of Nck for ligand binding. Cell Signal
  85. (2006). Requirement of Nck adaptors for actin dynamics and cell migration stimulated by platelet-derived growth factor B. Proc Natl Acad Sci USA
  86. (2005). Role of Sam68 as an adaptor protein in signal transduction. Cell Mol Life Sci
  87. (2003). Sam68 RNA binding protein is an in vivo substrate for protein arginine N-methyltransferase 1. Mol Biol Cell
  88. (1990). Samelson LE and Singer A: Inhibition of T cell receptor expression and function in immature CD4+CD8+ cells by CD4. Science
  89. (2003). SAP couples Fyn to SLAM immune receptors. Nat Cell Biol
  90. (2007). Secretory lysosomes and their cargo in T and NK cells. Immunol Lett
  91. (2000). Skolnik EY: Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation. Mol Cell Biol
  92. (2003). SLP-76 coordinates Nckdependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/Cdc42-dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact site.
  93. (2008). Specificity determinants of a novel Nck interaction with the juxtamembrane domain of the epidermal growth factor receptor. Biochemistry
  94. (2005). Src and FAK kinases cooperate to phosphorylate paxillin kinase linker, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Mol Biol Cell
  95. (2001). Src homology 3 domaindependent interaction of Nck-2 with insulin receptor substrate-1. Biochem J
  96. (2002). Src homology region 2 domaincontaining phosphatase 1 positively regulates B cell receptor-induced apoptosis by modulating association of B cell linker protein with Nck and activation of c-Jun NH2-terminal kinase.
  97. (2002). Src-induced phosphorylation of caveolin-2 on tyrosine 19. Phospho-caveolin-2 (Tyr(P)19) is localized near focal adhesions, remains associated with lipid rafts/caveolae, but no longer forms a high molecular mass hetero-oligomer with caveolin-1.
  98. Src-like adaptor protein down-regulates T cell receptor (TCR)-CD3 expression by targeting TCRzeta for degradation. JC e l lB i o l2005,
  99. (2006). Src-like adaptor protein regulates TCR expression on thymocytes by linking the ubiquitin ligase c-Cbl to the TCR complex. Nat Immunol
  100. Structural and functional evidence that Nck interaction with CD3epsilon regulates T-cell receptor activity. JM o lB i o l2008,
  101. (2006). Structural insight into the binding diversity between the human Nck2 SH3 domains and proline-rich proteins. Biochemistry
  102. (1996). Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrin-mediated signaling in lymphocytes. JE x pM e d
  103. (2008). Sweep FC and Edwards DR: Distinct functions of natural ADAM-15 cytoplasmic domain variants in human mammary carcinoma. Mol Cancer Res
  104. (2004). Systematic identification of regulatory proteins critical for T-cell activation. JB i o l2003,
  105. (2008). T cell receptor engagement triggers its CD3epsilon and CD3zeta subunits to adopt a compact, locked conformation. PLoS ONE
  106. (1998). Tan TH and Feller SM: The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins. Oncogene
  107. (2007). Tasken K and Saksela K: Reciprocal regulation of SH3 and SH2 domain binding via tyrosine phosphorylation of a common site in CD3epsilon.
  108. The adaptor protein
  109. (2006). The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse. Proc Natl Acad Sci USA
  110. (1996). The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase
  111. (2005). The CD3epsilon proline-rich sequence, and its interaction with Nck, is not required for T cell development and function.
  112. (1984). The major histocompatibility complexrestricted antigen receptor on T cells: distribution on thymus and peripheral T cells. Cell
  113. (1997). The multiple endocrine neoplasia type 2B point mutation switches the specificity of the Ret tyrosine kinase towards cellular substrates that are susceptible to interact with Crk and Nck. Oncogene
  114. (2002). The Nck family of adapter proteins: regulators of actin cytoskeleton. Cell Signal
  115. (1997). The Nck SH2/SH3 adaptor protein is present in the nucleus and associates with the nuclear protein SAM68. Oncogene
  116. (2008). The proline-rich sequence of CD3epsilon controls T cell antigen receptor expression on and signaling potency in preselection CD4+CD8+ thymocytes. Nat Immunol
  117. (1992). The SH2 and SH3 domain-containing Nck protein is oncogenic and a common target for phosphorylation by different surface receptors. Mol Cell Biol
  118. (1998). The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene
  119. The tyrosine kinase ACK1 associates with clathrin-coated vesicles through a binding motif shared by arrestin and other adaptors. JB i o lC h e m2001,
  120. (1997). The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells.
  121. (2007). The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol
  122. The WiskottAldrich syndrome protein-interacting protein (WIP) binds to the adaptor protein Nck.
  123. (2006). The X-linked lymphoproliferative disease gene product SAP associates with PAK-interacting exchange factor and participates in T cell activation. Proc Natl Acad Sci USA
  124. (1996). Thrombin stimulates association of src homology domain containing adaptor protein Nck with pp125FAK.
  125. (1999). TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton.
  126. (1997). Toyoshima K and Akiyama T: Identification of a novel nuclear localization signal in Sam68. FEBS Lett
  127. (2004). Transmembrane adaptor proteins: organizers of immunoreceptor signalling. Nat Rev Immunol
  128. (1993). Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor. Mol Cell Biol
  129. (2001). Tyrosine phosphorylation of beta-dystroglycan at its WW domain binding motif, PPxY, recruits SH2 domain containing proteins. Biochemistry
  130. (1999). Tyrosine phosphorylation of p62(Dok) induced by cell adhesion and insulin: possible role in cell migration.
  131. (2009). Wiskott-Aldrich syndrome protein physically associates Cell Communication and Signaling
  132. (1994). Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene

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