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. 2009 Feb 2:7:1.
doi: 10.1186/1478-811X-7-1.

Nck adapter proteins: functional versatility in T cells

Marcus Lettau  1 , Jennifer Pieper, Ottmar Janssen
Affiliations

Nck adapter proteins: functional versatility in T cells

Marcus Lettau et al. Cell Commun Signal. .

Abstract

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 CD3epsilon 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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Figures

Figure 1
Figure 1
Modular composition of Nck adapter proteins. Nck adapters are proteins of 47 kDa that are built of three SH3 domains and a C-terminal SH2 domain linked by small spacer regions. Nck1 displays 68% amino acid identity to Nck2. As indicated in the figure, the differences are mainly located in the linker regions between the interaction modules, whereas the individual SH2 and SH3 domains show a high degree of homology. Modular domains of Nck1 (NP_006140) and Nck2 (AAH07195) have been assigned using the simple modular architecture research tool SMART . The sequence homology between the interaction modules and the linker regions was determined using the SIM alignment tool for protein sequences . Percent values indicate the degree of identity of the respective regions.
Figure 2
Figure 2
TCR-induced actin-reorganization: Nck binding to phosphorylated Slp76. T cell activation is initiated by antigen-presenting cells (APCs) containing stimulatory MHC-peptide complexes. Src family protein tyrosine kinases mediate phosphorylation of TCR associated ITAMs thereby creating docking sites for the Syk-type kinase ZAP70. After activation by Src kinases, ZAP70 phosphorylates LAT. LAT contains nine tyrosine residues which, when phosphorylated, act as docking sites for adaptor proteins such as Grb2 and Gads. Slp76 is recruited to the membrane-proximal activation complex through its interaction with the SH3 domains of LAT-associated Gads. Phosphorylated Slp76 associates with the SH2 domain of Nck. Nck then recruits the multidomain adapter protein WASP. The GEF Vav, which is also recruited by Slp76, promotes the GTP-loading of the small Rho-GTPase Cdc42 that is critically involved in WASP activation. WASP then activates the Arp2/3 complex that initiates the formation of branched actin filament networks.
Figure 3
Figure 3
Suggested model for the function of the CD3ε PRS in double-positive thymocytes. (A) Nck associates with CD3ε in the absence of pMHC and recruits Lck, which phosphorylates TCRζ. Subsequently, phosphorylated TCRζ recruits SLAP, and SLAP-associated c-Cbl ubiquitinates (Ub) TCRζ. This leads to the degradation of TCRζ and thus increases the TCR sampling rate. (B) pMHC-mediated ligation of the TCR results in more complete phosphorylation of the CD3 ITAMS. In this context, the interaction of CD3ε-bound Nck with Lck may be necessary to prime the system and allow CD4 coreceptor-dependent Lck to initiate a full activation response with phosphorylation of the CD3ε ITAMS. This results in the recruitment of ZAP70, the dissociation of Nck and SLAP and thus the stabilization of TCR surface expression. (Figure accords with models suggested in [59]).
Figure 4
Figure 4
Subcellular localization of Nck and the death factor FasL in conjugates of Jurkat T cells and EBV-transformed B-LCL. Upon target cell recognition the death factor FasL is transported to the cytotoxic immunological synapse where it colocalizes with Nck. Jurkat T cells were transiently transfected with FasL, cocultured with superantigen-pulsed B-LCL (*, B lymphoblastoid cell line)), fixed, permeabilized and stained for FasL with anti-FasL mAb NOK-1 and respective AlexaFluor488-conjugated secondary antibodies and for Nck with an anti-Nck pAb and corresponding AlexaFluor546-conjugated secondary reagents.
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