NCK1
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| Location (UCSC) | Chr 3: 136.86 – 136.95 Mb | Chr 9: 100.37 – 100.43 Mb | |||||||
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Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.[5][6]
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.[7]
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.[8]
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.[9]
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.[10]
Interactions
NCK1 has been shown to interact with:
- CBL,[11][13]
- DNM1,[14]
- DAG1,[15]
- EIF2B2,[16]
- EPHB1,[17]
- EGFR,[18][19]
- KHDRBS1,[18][20]
- LCP2,[21][22]
- MAP4K1,[23][24]
- MAP4K4,[25]
- MINK1,[26]
- NCKIPSD,[27]
- NEDD9,[28]
- PAK1,[29][30][31]
- PDGFRB,[19][29]
- PKN2,[29][32]
- PTK2,[28][33]
- RASA1,[34]
- RICS,[35]
- RRAS,[36]
- SOCS7,[17]
- SOS1,[14][29][37][38]
- TBK1,[39]
- WASL,[40]
- WIPF1,[41] and
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000158092 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032475 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 7806213.
- PMID 9737977.
- ^ "Entrez Gene: NCK1 NCK adaptor protein 1".
- ^ 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.
- ^ 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.
- ^ 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.
- ^ PMID 11494134.
- PMID 7926767.
- S2CID 18340540.
- ^ PMID 10206341.
- PMID 11724572.
- PMID 11959995.
- ^ PMID 9344857.
- ^ PMID 9362449.
- ^ PMID 1333047.
- S2CID 21853774.
- S2CID 24678709.
- PMID 10229072.
- PMID 9891069.
- PMID 11279207.
- PMID 9135144.
- PMID 15469942.
- PMID 11278500.
- ^ PMID 8879209.
- ^ PMID 10026169.
- PMID 11157752.
- PMID 8824201.
- PMID 8910519.
- PMID 11950595.
- PMID 21664272.
- PMID 12819203.
- PMID 10671570.
- PMID 7862111.
- PMID 8810325.
- PMID 7706279.
- PMID 11340081.
- PMID 9694849.
- PMID 10747096.
- PMID 12135674.
- PMID 7565724.
Further reading
- Iwata S, Ohashi Y, Kamiguchi K, Morimoto C (2000). "Beta 1-integrin-mediated cell signaling in T lymphocytes". J. Dermatol. Sci. 23 (2): 75–86. PMID 10808124.
- 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. 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. 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. 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. 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. 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. PMID 7862111.
- Vorobieva N, Protopopov A, Protopopova M, Kashuba V, Allikmets RL, Modi W, Zabarovsky ER, Klein G, Kisselev L, Graphodatsky A (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. PMID 7956370.
- Kitamura T, Kitamura Y, Yonezawa K, Totty NF, Gout I, Hara K, Waterfield MD, Sakaue M, Ogawa W, Kasuga M (1996). "Molecular cloning of p125Nap1, a protein that associates with an SH3 domain of Nck". Biochem. Biophys. Res. Commun. 219 (2): 509–14. 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. PMID 8810325.
- Bokoch GM, Wang Y, Bohl BP, Sells MA, Quilliam LA, Knaus UG (1996). "Interaction of the Nck adapter protein with p21-activated kinase (PAK1)". J. Biol. Chem. 271 (42): 25746–9. PMID 8824201.
- Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C (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. PMID 8879209.
- Roche S, McGlade J, Jones M, Gish GD, Pawson T, Courtneidge SA (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. PMID 8890167.
- Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ (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. PMID 8910519.
- Lussier G, Larose L (1997). "A casein kinase I activity is constitutively associated with Nck". J. Biol. Chem. 272 (5): 2688–94. 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. S2CID 21853774.
- 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. S2CID 16173970.
- Su YC, Han J, Xu S, Cobb M, Skolnik EY (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. PMID 9135144.
External links
- Nck1 Info with links in the Cell Migration Gateway Archived 11 December 2014 at the Wayback Machine
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