NCK1 explained

Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.^{[1] [2]}

Gene

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.

Function

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.^[3]

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.^[4]

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 neurectomy-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.^[5]

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.^[6]

Interactions

NCK1 has been shown to interact with:

• ABL1,^{[7] [8]}
• CBL,^{[7] [9]}
• DNM1,^[10]
• DAG1,^[11]
• EIF2B2,^[12]
• EPHB1,^[13]
• EGFR,^[14]
• KHDRBS1,^{[15] [16]}
• LCP2,^{[17] [18]}
• MAP4K1,^{[19] [20]}
• MAP4K4,^[21]
• MINK1,^[22]
• NCKIPSD,^[23]
• NEDD9,
• PAK1,^{[24] [25]}
• PDGFRB,^[14]
• PKN2,^[26]
• PTK2,^{[27] [28]}
• RASA1,^[29]
• RICS,^[30]
• RRAS,^[31]
• SOCS7,^[13]
• SOS1,^{[10] [32] [33]}
• TBK1,^[34]
• WASL,^[35]
• WIPF1,^[36] and
• WAS.^{[37] [38] [39] [40]}

See also

• Signal transducing adaptor protein
• Receptor tyrosine kinase
• Ras superfamily

Further reading

• Iwata S, Ohashi Y, Kamiguchi K, Morimoto C . Beta 1-integrin-mediated cell signaling in T lymphocytes . J. Dermatol. Sci. . 23 . 2 . 75–86 . 2000 . 10808124 . 10.1016/S0923-1811(99)00096-1 .
• Park D, Rhee SG . Phosphorylation of Nck in response to a variety of receptors, phorbol myristate acetate, and cyclic AMP . Mol. Cell. Biol. . 12 . 12 . 5816–23 . 1992 . 1333046 . 360521 . 10.1128/MCB.12.12.5816 .
• Meisenhelder J, Hunter T . 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 . 1992 . 1448108 . 360524 . 10.1128/MCB.12.12.5843 .
• Lehmann JM, Riethmüller G, Johnson JP . Nck, a melanoma cDNA encoding a cytoplasmic protein consisting of the src homology units SH2 and SH3 . Nucleic Acids Res. . 18 . 4 . 1048 . 1990 . 2107526 . 330365 . 10.1093/nar/18.4.1048 .
• Rivero-Lezcano OM, Sameshima JH, Marcilla A, Robbins KC . Physical association between Src homology 3 elements and the protein product of the c-cbl proto-oncogene . J. Biol. Chem. . 269 . 26 . 17363–6 . 1994 . 10.1016/S0021-9258(17)32443-2 . 7517397 . free .
• Rivero-Lezcano OM, Marcilla A, Sameshima JH, Robbins KC . Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains . Mol. Cell. Biol. . 15 . 10 . 5725–31 . 1995 . 7565724 . 230823 . 10.1128/MCB.15.10.5725 .
• Chou MM, Hanafusa H . 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 . 1995 . 7706279 . 10.1074/jbc.270.13.7359 . free .
• Hu Q, Milfay D, Williams LT . Binding of NCK to SOS and activation of ras-dependent gene expression . Mol. Cell. Biol. . 15 . 3 . 1169–74 . 1995 . 7862111 . 230339 . 10.1128/MCB.15.3.1169 .
• Vorobieva N, Protopopov A, Protopopova M, Kashuba V, Allikmets RL, Modi W, Zabarovsky ER, Klein G, Kisselev L, Graphodatsky A . 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 . 1994 . 7956370 . 10.1159/000133898 .
• Kitamura T, Kitamura Y, Yonezawa K, Totty NF, Gout I, Hara K, Waterfield MD, Sakaue M, Ogawa W, Kasuga M . Molecular cloning of p125Nap1, a protein that associates with an SH3 domain of Nck . Biochem. Biophys. Res. Commun. . 219 . 2 . 509–14 . 1996 . 8605018 . 10.1006/bbrc.1996.0264 . 20.500.14094/D1001555 . free .
• Okada S, Pessin JE . 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 . 1996 . 8810325 . 10.1074/jbc.271.41.25533 . free.
• Bokoch GM, Wang Y, Bohl BP, Sells MA, Quilliam LA, Knaus UG . Interaction of the Nck adapter protein with p21-activated kinase (PAK1) . J. Biol. Chem. . 271 . 42 . 25746–9 . 1996 . 8824201 . 10.1074/jbc.271.42.25746 . free .
• Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C . 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 . 1996 . 8879209 . 2192828 . 10.1084/jem.184.4.1365 .
• Roche S, McGlade J, Jones M, Gish GD, Pawson T, Courtneidge SA . 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 . 1996 . 8890167 . 452231 . 10.1002/j.1460-2075.1996.tb00874.x .
• Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ . 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 . 1997 . 8910519 . 10.1074/jbc.271.46.28772 . free .
• Lussier G, Larose L . A casein kinase I activity is constitutively associated with Nck . J. Biol. Chem. . 272 . 5 . 2688–94 . 1997 . 9006905 . 10.1074/jbc.272.5.2688 . free .
• Lawe DC, Hahn C, Wong AJ . The Nck SH2/SH3 adaptor protein is present in the nucleus and associates with the nuclear protein SAM68 . Oncogene . 14 . 2 . 223–31 . 1997 . 9010224 . 10.1038/sj.onc.1200821 . 21853774 .
• Lu W, Katz S, Gupta R, Mayer BJ . Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck . Curr. Biol. . 7 . 2 . 85–94 . 1997 . 9024622 . 10.1016/S0960-9822(06)00052-2 . 16173970 . free . 1997CBio....7...85L .
• Su YC, Han J, Xu S, Cobb M, Skolnik EY . 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 . 1997 . 9135144 . 1169726 . 10.1093/emboj/16.6.1279 .

External links

• Nck1 Info with links in the Cell Migration Gateway

Notes and References

1. Huebner K, Kastury K, Druck T, Salcini AE, Lanfrancone L, Pelicci G, Lowenstein E, Li W, Park SH, Cannizzaro L . Chromosome locations of genes encoding human signal transduction adapter proteins, Nck (NCK), Shc (SHC1), and Grb2 (GRB2) . Genomics . 22 . 2 . 281–7 . January 1995 . 7806213 . 10.1006/geno.1994.1385 . free .
2. Chen M, She H, Davis EM, Spicer CM, Kim L, Ren R, Le Beau MM, Li W . Identification of Nck family genes, chromosomal localization, expression, and signaling specificity . J Biol Chem . 273 . 39 . 25171–8 . October 1998 . 9737977 . 10.1074/jbc.273.39.25171 . free .
3. Web site: Entrez Gene: NCK1 NCK adaptor protein 1.
4. Latreille, M., Laberge, M., Bourret, G., Yamani, L., & Larose, L. (2011). Deletion of Nck1 attenuates hepatic ER stress signaling and improves glucose tolerance and insulin signaling in liver of obese mice. American Journal of Physiology, 300(3), 423-424-434.
5. 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.
6. Chaki, S. P., & Rivera, G. M. (2013 May-Jun). Integration of signaling and cytoskeletal remodeling by nck in directional cell migration. [Integration of signaling and cytoskeletal remodeling by Nck in directional cell migration.] Bioarchitecture, 3(3), 57-58-63.
7. Miyoshi-Akiyama T, Aleman LM, Smith JM, Adler CE, Mayer BJ . Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor . Oncogene . 20 . 30 . 4058–69 . July 2001 . 11494134 . 10.1038/sj.onc.1204528 . free .
8. Ren R, Ye ZS, Baltimore D . Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites . Genes Dev. . 8 . 7 . 783–95 . April 1994 . 7926767 . 10.1101/gad.8.7.783 . free .
9. Erdreich-Epstein A, Liu M, Kant AM, Izadi KD, Nolta JA, Durden DL . Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages . J. Leukoc. Biol. . 65 . 4 . 523–34 . April 1999 . 10204582 . 10.1002/jlb.65.4.523. 18340540 .
10. Wunderlich L, Faragó A, Buday L . Characterization of interactions of Nck with Sos and dynamin . Cell. Signal. . 11 . 1 . 25–9 . January 1999 . 10206341 . 10.1016/S0898-6568(98)00027-8 .
11. Sotgia F, Lee H, Bedford MT, Petrucci T, Sudol M, Lisanti MP . Tyrosine phosphorylation of beta-dystroglycan at its WW domain binding motif, PPxY, recruits SH2 domain containing proteins . Biochemistry . 40 . 48 . 14585–92 . December 2001 . 11724572 . 10.1021/bi011247r .
12. Kebache S, Zuo D, Chevet E, Larose L . Modulation of protein translation by Nck-1 . Proc. Natl. Acad. Sci. U.S.A. . 99 . 8 . 5406–11 . April 2002 . 11959995 . 122782 . 10.1073/pnas.082483399 . 2002PNAS...99.5406K . free .
13. Matuoka K, Miki H, Takahashi K, Takenawa T . A novel ligand for an SH3 domain of the adaptor protein Nck bears an SH2 domain and nuclear signaling motifs . Biochem. Biophys. Res. Commun. . 239 . 2 . 488–92 . October 1997 . 9344857 . 10.1006/bbrc.1997.7492 .
14. Li W, Hu P, Skolnik EY, Ullrich A, Schlessinger J . The SH2 and SH3 domain-containing Nck protein is oncogenic and a common target for phosphorylation by different surface receptors . Mol. Cell. Biol. . 12 . 12 . 5824–33 . December 1992 . 1333047 . 360522 . 10.1128/MCB.12.12.5824 .
15. Tang J, Feng GS, Li W . Induced direct binding of the adapter protein Nck to the GTPase-activating protein-associated protein p62 by epidermal growth factor . Oncogene . 15 . 15 . 1823–32 . October 1997 . 9362449 . 10.1038/sj.onc.1201351 .
16. Lawe DC, Hahn C, Wong AJ . The Nck SH2/SH3 adaptor protein is present in the nucleus and associates with the nuclear protein SAM68 . Oncogene . 14 . 2 . 223–31 . January 1997 . 9010224 . 10.1038/sj.onc.1200821 . 21853774 .
17. Shim EK, Moon CS, Lee GY, Ha YJ, Chae SK, Lee JR . Association of the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) with the p85 subunit of phosphoinositide 3-kinase . FEBS Lett. . 575 . 1–3 . 35–40 . September 2004 . 15388330 . 10.1016/j.febslet.2004.07.090 . 24678709 . 2004FEBSL.575...35S .
18. Wunderlich L, Faragó A, Downward J, Buday L . Association of Nck with tyrosine-phosphorylated SLP-76 in activated T lymphocytes . Eur. J. Immunol. . 29 . 4 . 1068–75 . April 1999 . 10229072 . 10.1002/(SICI)1521-4141(199904)29:04<1068::AID-IMMU1068>3.0.CO;2-P . free .
19. Ling P, Yao Z, Meyer CF, Wang XS, Oehrl W, Feller SM, Tan TH . Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase . Mol. Cell. Biol. . 19 . 2 . 1359–68 . February 1999 . 9891069 . 116064 . 10.1128/MCB.19.2.1359.
20. Ling P, Meyer CF, Redmond LP, Shui JW, Davis B, Rich RR, Hu MC, Wange RL, Tan TH . Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling . J. Biol. Chem. . 276 . 22 . 18908–14 . June 2001 . 11279207 . 10.1074/jbc.M101485200 . free .
21. Su YC, Han J, Xu S, Cobb M, Skolnik EY . 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 . March 1997 . 9135144 . 1169726 . 10.1093/emboj/16.6.1279 .
22. Hu Y, Leo C, Yu S, Huang BC, Wang H, Shen M, Luo Y, Daniel-Issakani S, Payan DG, Xu X . Identification and functional characterization of a novel human misshapen/Nck interacting kinase-related kinase, hMINK beta . J. Biol. Chem. . 279 . 52 . 54387–97 . December 2004 . 15469942 . 10.1074/jbc.M404497200 . free .
23. Lim CS, Park ES, Kim DJ, Song YH, Eom SH, Chun JS, Kim JH, Kim JK, Park D, Song WK . 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 . April 2001 . 11278500 . 10.1074/jbc.M009411200 . free .
24. Ku GM, Yablonski D, Manser E, Lim L, Weiss A . 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 . February 2001 . 11157752 . 133476 . 10.1093/emboj/20.3.457 .
25. Bokoch GM, Wang Y, Bohl BP, Sells MA, Quilliam LA, Knaus UG . Interaction of the Nck adapter protein with p21-activated kinase (PAK1) . J. Biol. Chem. . 271 . 42 . 25746–9 . October 1996 . 8824201 . 10.1074/jbc.271.42.25746 . free .
26. Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ . 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 . November 1996 . 8910519 . 10.1074/jbc.271.46.28772 . free .
27. Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C . 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 . October 1996 . 8879209 . 2192828 . 10.1084/jem.184.4.1365 .
28. Goicoechea SM, Tu Y, Hua Y, Chen K, Shen TL, Guan JL, Wu C . Nck-2 interacts with focal adhesion kinase and modulates cell motility . Int. J. Biochem. Cell Biol. . 34 . 7 . 791–805 . July 2002 . 11950595 . 10.1016/S1357-2725(02)00002-X .
29. Ger M, Zitkus Z, Valius M . Adaptor protein Nck1 interacts with p120 Ras GTPase-activating protein and regulates its activity . Cell. Signal. . 23 . 10 . 1651–8 . October 2011 . 21664272 . 10.1016/j.cellsig.2011.05.019 .
30. Zhao C, Ma H, Bossy-Wetzel E, Lipton SA, Zhang Z, Feng GS . GC-GAP, a Rho family GTPase-activating protein that interacts with signaling adapters Gab1 and Gab2 . J. Biol. Chem. . 278 . 36 . 34641–53 . September 2003 . 12819203 . 10.1074/jbc.M304594200 . free .
31. Wang B, Zou JX, Ek-Rylander B, Ruoslahti E . 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 . February 2000 . 10671570 . 10.1074/jbc.275.7.5222 . free .
32. Hu Q, Milfay D, Williams LT . Binding of NCK to SOS and activation of ras-dependent gene expression . Mol. Cell. Biol. . 15 . 3 . 1169–74 . March 1995 . 7862111 . 230339 . 10.1128/MCB.15.3.1169.
33. Okada S, Pessin JE . 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 . October 1996 . 8810325 . 10.1074/jbc.271.41.25533 . free.
34. Chou MM, Hanafusa H . 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 . March 1995 . 7706279 . 10.1074/jbc.270.13.7359 . free .
35. Rohatgi R, Nollau P, Ho HY, Kirschner MW, Mayer BJ . Nck and phosphatidylinositol 4,5-bisphosphate synergistically activate actin polymerization through the N-WASP-Arp2/3 pathway . J. Biol. Chem. . 276 . 28 . 26448–52 . July 2001 . 11340081 . 10.1074/jbc.M103856200 . free .
36. Antón IM, Lu W, Mayer BJ, Ramesh N, Geha RS . The Wiskott-Aldrich syndrome protein-interacting protein (WIP) binds to the adaptor protein Nck . J. Biol. Chem. . 273 . 33 . 20992–5 . August 1998 . 9694849 . 10.1074/jbc.273.33.20992 . free .
37. 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. . 274 . 9 . 5542–9 . February 1999 . 10026169 . 10.1074/jbc.274.9.5542 . free .
38. Krause M, Sechi AS, Konradt M, Monner D, Gertler FB, Wehland J . 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 . April 2000 . 10747096 . 2175102 . 10.1083/jcb.149.1.181 .
39. Okabe S, Fukuda S, Broxmeyer HE . Activation of Wiskott-Aldrich syndrome protein and its association with other proteins by stromal cell-derived factor-1alpha is associated with cell migration in a T-lymphocyte line . Exp. Hematol. . 30 . 7 . 761–6 . July 2002 . 12135674 . 10.1016/S0301-472X(02)00823-8 . free .
40. Rivero-Lezcano OM, Marcilla A, Sameshima JH, Robbins KC . Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains . Mol. Cell. Biol. . 15 . 10 . 5725–31 . October 1995 . 7565724 . 230823 . 10.1128/MCB.15.10.5725.