|NCK adaptor protein 1|
PDB rendering based on 2ci8.
|Symbols||; NCK; NCKalpha; nck-1|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated from a human melanoma cDNA library using a monoclonal antibody produced against the human melanoma-associated antigen. The Nck family has two known members in human cells (Nck-1/Nckalpha and NcK2/NcKbeta), two in mouse cells (mNckalpha and mNckbeta/Grb4) and one in drosophila (Dock means dreadlocks-ortholog).
The two murine gene products exhibit 68% amino acid identity to one another, with most of the sequence variation being located to the linker regions between the SH3 and SH2 domains, and are 96% identical to their human counterparts. While human nck-1 gene has been localised to the 3q21 locus of chromosome 3, the nck-2 gene can be found on chromosome 2 at the 2q12 locus.
The protein encoded by this gene is one of the signaling and transforming proteins containing Src homology 2 and 3 (SH2 and SH3) domains. It is located in the cytoplasm and is an adaptor protein involved in transducing signals from receptor tyrosine kinases to downstream signal recipients such as RAS.
Nck1 has been linked to glucose tolerance and insulin signaling within certain tissues, namely the liver, in obese mice. A deletion of the protein also causes a decrease of ER stress signaling within these obese cells, which is normally increased by the excessive fat. This stress causes expression of the unfolded protein response pathway, which leads to a decrease in glucose tolerance and inactivation of insulin signaling in certain cell types. This renewed glucose tolerance and insulin signaling is caused by the inhibition of the unfolded protein response pathway, particularly the protein IRE1alpha, and its subsequent phosphorylation of IRS-1 that causes insulin signaling to be blocked. IRE1alpha is involved with the JNK pathway that is responsible for the phosphorylation of IRS-1. Nck1 regulates the activation of IRE1alpha within the pathway and when removed from the pathway disrupts activation. This means that Nck1 has an interaction with the UPR and that a deletion can cause a decrease in the stress pathway from the ER in the mice. These deficient, obese mice also show increased insulin-induced phosphorylation of PKB within the liver but do not possess the same expression in adipose tissues or skeletal muscles. This evidence points to the pathway being ER stress induced within liver tissue. 
Nck1 has been shown to be associated with bone mass. A deficiency in Nck1, which is shown to reduce ER stress in obese mice, also accelerates unloading-induced osteoporosis caused by mechanical stress. This seems to suggest that would be a crucial protein involved with bone metabolism and that retention of bone tissue by a protein as yet unknown. Nck1 expression increased twofold when involved with nerectomy-based unloading osteoporosis. This then follows that in a deficient organism this upregulation would not be possible and thus the body would have increased bone loss due to the lack of expression of Nck1 to deal with the stress, which is what happens in vivo. This acceleration of bone loss leads researchers to believe that the pathway for bone metabolism is highly regulated by several proteins that have yet to be discovered or incorporated into a schema.
Nck1 is involved with cellular remodeling via the WASp/Arp2/3 complex to coordinate actin cytoskeletal remodeling. The WASp binds to the SH3 domains within the N-terminus of the protein and after Nck1 has been activated by the signal from the ligand binding to a receptor tyrosine kinase and then uses the WASp/Arp2/3 complex to reorganize the actin cytoskeleton and cause the polarization of the cell as well as promote directional migration via pseudopodia. The reorganization of this cytoskeleton is caused by different Rho GTPases being moved to different locations within the cell, primarily to the leading edge, and strengthening the bonds with extracellular matrix components to induce motion. 
NCK1 has been shown to interact with:
- WIPF1, and
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- Aryal, A. C., Miyai, K., Hayata, T., Notomi, T., Nakamoto, T., Pawson, T., et al. (2013). Nck1 deficiency accelerates unloading-induced bone loss.. Journal of Cell Physiology, 228(7), 1397-1398-1403.
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- Lawe DC, Hahn C, Wong AJ (January 1997). "The Nck SH2/SH3 adaptor protein is present in the nucleus and associates with the nuclear protein SAM68". Oncogene 14 (2): 223–31. doi:10.1038/sj.onc.1200821. PMID 9010224.
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- Su YC, Han J, Xu S, Cobb M, Skolnik EY (March 1997). "NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain". EMBO J. 16 (6): 1279–90. doi:10.1093/emboj/16.6.1279. PMC 1169726. PMID 9135144.
- Hu Y, Leo C, Yu S, Huang BC, Wang H, Shen M, Luo Y, Daniel-Issakani S, Payan DG, Xu X (December 2004). "Identification and functional characterization of a novel human misshapen/Nck interacting kinase-related kinase, hMINK beta". J. Biol. Chem. 279 (52): 54387–97. doi:10.1074/jbc.M404497200. PMID 15469942.
- Lim CS, Park ES, Kim DJ, Song YH, Eom SH, Chun JS, Kim JH, Kim JK, Park D, Song WK (April 2001). "SPIN90 (SH3 protein interacting with Nck, 90 kDa), an adaptor protein that is developmentally regulated during cardiac myocyte differentiation". J. Biol. Chem. 276 (16): 12871–8. doi:10.1074/jbc.M009411200. PMID 11278500.
- Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C (October 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". J. Exp. Med. 184 (4): 1365–75. doi:10.1084/jem.184.4.1365. PMC 2192828. PMID 8879209.
- Braverman LE, Quilliam LA (February 1999). "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. 274 (9): 5542–9. doi:10.1074/jbc.274.9.5542. PMID 10026169.
- Ku GM, Yablonski D, Manser E, Lim L, Weiss A (February 2001). "A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT". EMBO J. 20 (3): 457–65. doi:10.1093/emboj/20.3.457. PMC 133476. PMID 11157752.
- Bokoch GM, Wang Y, Bohl BP, Sells MA, Quilliam LA, Knaus UG (October 1996). "Interaction of the Nck adapter protein with p21-activated kinase (PAK1)". J. Biol. Chem. 271 (42): 25746–9. doi:10.1074/jbc.271.42.25746. PMID 8824201.
- Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ (November 1996). "Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signaling". J. Biol. Chem. 271 (46): 28772–6. doi:10.1074/jbc.271.46.28772. PMID 8910519.
- Goicoechea SM, Tu Y, Hua Y, Chen K, Shen TL, Guan JL, Wu C (July 2002). "Nck-2 interacts with focal adhesion kinase and modulates cell motility". Int. J. Biochem. Cell Biol. 34 (7): 791–805. doi:10.1016/S1357-2725(02)00002-X. PMID 11950595.
- Ger M, Zitkus Z, Valius M (October 2011). "Adaptor protein Nck1 interacts with p120 Ras GTPase-activating protein and regulates its activity". Cell. Signal. 23 (10): 1651–8. doi:10.1016/j.cellsig.2011.05.019. PMID 21664272.
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- Wang B, Zou JX, Ek-Rylander B, Ruoslahti E (February 2000). "R-Ras contains a proline-rich site that binds to SH3 domains and is required for integrin activation by R-Ras". J. Biol. Chem. 275 (7): 5222–7. doi:10.1074/jbc.275.7.5222. PMID 10671570.
- Hu Q, Milfay D, Williams LT (March 1995). "Binding of NCK to SOS and activation of ras-dependent gene expression". Mol. Cell. Biol. 15 (3): 1169–74. PMC 230339. PMID 7862111.
- Okada S, Pessin JE (October 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". J. Biol. Chem. 271 (41): 25533–8. doi:10.1074/jbc.271.41.25533. PMID 8810325.
- Chou MM, Hanafusa H (March 1995). "A novel ligand for SH3 domains. The Nck adaptor protein binds to a serine/threonine kinase via an SH3 domain". J. Biol. Chem. 270 (13): 7359–64. doi:10.1074/jbc.270.13.7359. PMID 7706279.
- Rohatgi R, Nollau P, Ho HY, Kirschner MW, Mayer BJ (July 2001). "Nck and phosphatidylinositol 4,5-bisphosphate synergistically activate actin polymerization through the N-WASP-Arp2/3 pathway". J. Biol. Chem. 276 (28): 26448–52. doi:10.1074/jbc.M103856200. PMID 11340081.
- Antón IM, Lu W, Mayer BJ, Ramesh N, Geha RS (August 1998). "The Wiskott-Aldrich syndrome protein-interacting protein (WIP) binds to the adaptor protein Nck". J. Biol. Chem. 273 (33): 20992–5. doi:10.1074/jbc.273.33.20992. PMID 9694849.
- Krause M, Sechi AS, Konradt M, Monner D, Gertler FB, Wehland J (April 2000). "Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton". J. Cell Biol. 149 (1): 181–94. doi:10.1083/jcb.149.1.181. PMC 2175102. PMID 10747096.
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- Rivero-Lezcano OM, Marcilla A, Sameshima JH, Robbins KC (October 1995). "Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains". Mol. Cell. Biol. 15 (10): 5725–31. PMC 230823. PMID 7565724.
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- Park D, Rhee SG (1992). "Phosphorylation of Nck in response to a variety of receptors, phorbol myristate acetate, and cyclic AMP". Mol. Cell. Biol. 12 (12): 5816–23. PMC 360521. PMID 1333046.
- Meisenhelder J, Hunter T (1992). "The SH2/SH3 domain-containing protein Nck is recognized by certain anti-phospholipase C-gamma 1 monoclonal antibodies, and its phosphorylation on tyrosine is stimulated by platelet-derived growth factor and epidermal growth factor treatment". Mol. Cell. Biol. 12 (12): 5843–56. PMC 360524. PMID 1448108.
- Lehmann JM, Riethmüller G, Johnson JP (1990). "Nck, a melanoma cDNA encoding a cytoplasmic protein consisting of the src homology units SH2 and SH3". Nucleic Acids Res. 18 (4): 1048. doi:10.1093/nar/18.4.1048. PMC 330365. PMID 2107526.
- Rivero-Lezcano OM, Sameshima JH, Marcilla A, Robbins KC (1994). "Physical association between Src homology 3 elements and the protein product of the c-cbl proto-oncogene". J. Biol. Chem. 269 (26): 17363–6. PMID 7517397.
- Rivero-Lezcano OM, Marcilla A, Sameshima JH, Robbins KC (1995). "Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains". Mol. Cell. Biol. 15 (10): 5725–31. PMC 230823. PMID 7565724.
- Chou MM, Hanafusa H (1995). "A novel ligand for SH3 domains. The Nck adaptor protein binds to a serine/threonine kinase via an SH3 domain". J. Biol. Chem. 270 (13): 7359–64. doi:10.1074/jbc.270.13.7359. PMID 7706279.
- Hu Q, Milfay D, Williams LT (1995). "Binding of NCK to SOS and activation of ras-dependent gene expression". Mol. Cell. Biol. 15 (3): 1169–74. PMC 230339. PMID 7862111.
- Vorobieva N, Protopopov A, Protopopova M et al. (1994). "Localization of human ARF2 and NCK genes and 13 other NotI-linking clones to chromosome 3 by fluorescence in situ hybridization". Cytogenet. Cell Genet. 68 (1–2): 91–4. doi:10.1159/000133898. PMID 7956370.
- Kitamura T, Kitamura Y, Yonezawa K et al. (1996). "Molecular cloning of p125Nap1, a protein that associates with an SH3 domain of Nck". Biochem. Biophys. Res. Commun. 219 (2): 509–14. doi:10.1006/bbrc.1996.0264. PMID 8605018.
- Okada S, Pessin JE (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". J. Biol. Chem. 271 (41): 25533–8. doi:10.1074/jbc.271.41.25533. PMID 8810325.
- Bokoch GM, Wang Y, Bohl BP et al. (1996). "Interaction of the Nck adapter protein with p21-activated kinase (PAK1)". J. Biol. Chem. 271 (42): 25746–9. doi:10.1074/jbc.271.42.25746. PMID 8824201.
- Minegishi M, Tachibana K, Sato T et al. (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". J. Exp. Med. 184 (4): 1365–75. doi:10.1084/jem.184.4.1365. PMC 2192828. PMID 8879209.
- Roche S, McGlade J, Jones M et al. (1996). "Requirement of phospholipase C gamma, the tyrosine phosphatase Syp and the adaptor proteins Shc and Nck for PDGF-induced DNA synthesis: evidence for the existence of Ras-dependent and Ras-independent pathways". EMBO J. 15 (18): 4940–8. PMC 452231. PMID 8890167.
- Quilliam LA, Lambert QT, Mickelson-Young LA et al. (1997). "Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signaling". J. Biol. Chem. 271 (46): 28772–6. doi:10.1074/jbc.271.46.28772. PMID 8910519.
- Lussier G, Larose L (1997). "A casein kinase I activity is constitutively associated with Nck". J. Biol. Chem. 272 (5): 2688–94. doi:10.1074/jbc.272.5.2688. PMID 9006905.
- Lawe DC, Hahn C, Wong AJ (1997). "The Nck SH2/SH3 adaptor protein is present in the nucleus and associates with the nuclear protein SAM68". Oncogene 14 (2): 223–31. doi:10.1038/sj.onc.1200821. PMID 9010224.
- Lu W, Katz S, Gupta R, Mayer BJ (1997). "Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck". Curr. Biol. 7 (2): 85–94. doi:10.1016/S0960-9822(06)00052-2. PMID 9024622.
- Su YC, Han J, Xu S et al. (1997). "NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain". EMBO J. 16 (6): 1279–90. doi:10.1093/emboj/16.6.1279. PMC 1169726. PMID 9135144.