| Structural highlights
Function
[NCK1_HUMAN] Adapter protein which associates with tyrosine-phosphorylated growth factor receptors, such as KDR and PDGFRB, or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in the DNA damage response, not in the detection of the damage by ATM/ATR, but for efficient activation of downstream effectors, such as that of CHEK2. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling.[1] [2] [3] [TIR_ECO27] Multifunctional protein that is required for efficient pedestal formation in host epithelial cells during infection. The extracellular region acts as a receptor for bacterial intimin, allowing the bacterium to attach tightly to the host-cell surface. Simultaneously, the intracellular region initiates a signaling cascade in the host cell, which leads to actin polymerization and formation of actin pedestals at the sites of bacterial adhesion. In strain E2348/69, acts mainly via the host adaptor proteins NCK1 and NCK2. Once clustered and phosphorylated at Tyr-474, Tir binds to NCK proteins, which in turn bind and activate host WASL/N-WASP, leading to actin polymerization. Can also trigger an inefficient, NCK-independent pedestal formation. This pathway involves phosphorylation of Tyr-454 and probably a putative host adaptor. Acts also via direct binding to the host cytoskeletal protein alpha-actinin in a NCK- and phosphotyrosine-independent manner. This interaction may stabilize the pedestal, but is not essential for its formation.[4] [5] [6] [7] [8] [9]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Nck proteins are essential Src homology (SH) 2 and SH3 domain-bearing adapters that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. Two mammalian pathogens, enteropathogenic Escherichia coli and vaccinia virus, exploit Nck as part of their infection strategy. Conflicting data indicate potential differences in the recognition specificities of the SH2 domains of the isoproteins Nck1 (Nckalpha) and Nck2 (Nckbeta and Grb4). We have characterized the binding specificities of both SH2 domains and find them to be essentially indistinguishable. Crystal structures of both domains in complex with phosphopeptides derived from the enteropathogenic E. coli protein Tir concur in identifying highly conserved, specific recognition of the phosphopeptide. Differential peptide recognition can therefore not account for the preference of either Nck in particular signaling pathways. Binding studies using sequentially mutated, high affinity phosphopeptides establish the sequence variability tolerated in peptide recognition. Based on this binding motif, we identify potential new binding partners of Nck1 and Nck2 and confirm this experimentally for the Arf-GAP GIT1.
The phosphotyrosine peptide binding specificity of Nck1 and Nck2 Src homology 2 domains.,Frese S, Schubert WD, Findeis AC, Marquardt T, Roske YS, Stradal TE, Heinz DW J Biol Chem. 2006 Jun 30;281(26):18236-45. Epub 2006 Apr 24. PMID:16636066[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Braverman LE, Quilliam LA. Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck. J Biol Chem. 1999 Feb 26;274(9):5542-9. PMID:10026169
- ↑ Latreille M, Larose L. 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. J Biol Chem. 2006 Sep 8;281(36):26633-44. Epub 2006 Jul 11. PMID:16835242 doi:http://dx.doi.org/M513556200
- ↑ Kremer BE, Adang LA, Macara IG. Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7. Cell. 2007 Sep 7;130(5):837-50. PMID:17803907 doi:http://dx.doi.org/10.1016/j.cell.2007.06.053
- ↑ Kenny B. Phosphorylation of tyrosine 474 of the enteropathogenic Escherichia coli (EPEC) Tir receptor molecule is essential for actin nucleating activity and is preceded by additional host modifications. Mol Microbiol. 1999 Feb;31(4):1229-41. PMID:10096089
- ↑ Campellone KG, Rankin S, Pawson T, Kirschner MW, Tipper DJ, Leong JM. Clustering of Nck by a 12-residue Tir phosphopeptide is sufficient to trigger localized actin assembly. J Cell Biol. 2004 Feb 2;164(3):407-16. PMID:14757753 doi:http://dx.doi.org/10.1083/jcb.200306032
- ↑ Lommel S, Benesch S, Rohde M, Wehland J, Rottner K. Enterohaemorrhagic and enteropathogenic Escherichia coli use different mechanisms for actin pedestal formation that converge on N-WASP. Cell Microbiol. 2004 Mar;6(3):243-54. PMID:14764108
- ↑ Campellone KG, Leong JM. Nck-independent actin assembly is mediated by two phosphorylated tyrosines within enteropathogenic Escherichia coli Tir. Mol Microbiol. 2005 Apr;56(2):416-32. PMID:15813734 doi:http://dx.doi.org/10.1111/j.1365-2958.2005.04548.x
- ↑ Brady MJ, Campellone KG, Ghildiyal M, Leong JM. Enterohaemorrhagic and enteropathogenic Escherichia coli Tir proteins trigger a common Nck-independent actin assembly pathway. Cell Microbiol. 2007 Sep;9(9):2242-53. Epub 2007 May 23. PMID:17521329 doi:http://dx.doi.org/10.1111/j.1462-5822.2007.00954.x
- ↑ Kenny B, DeVinney R, Stein M, Reinscheid DJ, Frey EA, Finlay BB. Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells. Cell. 1997 Nov 14;91(4):511-20. PMID:9390560
- ↑ Frese S, Schubert WD, Findeis AC, Marquardt T, Roske YS, Stradal TE, Heinz DW. The phosphotyrosine peptide binding specificity of Nck1 and Nck2 Src homology 2 domains. J Biol Chem. 2006 Jun 30;281(26):18236-45. Epub 2006 Apr 24. PMID:16636066 doi:10.1074/jbc.M512917200
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