| Structural highlights
Disease
[HCK_HUMAN] Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity.[1] [2] Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation.[3] [4]
Function
[NEF_HV1A2] Factor of infectivity and pathogenicity, required for optimal virus replication. Alters numerous pathways of T-lymphocytes function and down-regulates immunity surface molecules in order to evade host defense and increase viral infectivity. Alters the functionality of other immunity cells, like dendritic cells, monocytes/macrophages and NK cells. One of the earliest and most abundantly expressed viral proteins (By similarity).[5] [6] [7] [8] [9] [10] In infected CD4(+) T-lymphocytes, down-regulates the surface MHC-I, mature MHC-II, CD4, CD28, CCR5 and CXCR4 molecules. Mediates internalization and degradation of host CD4 through the interaction of with the cytoplasmic tail of CD4, the recruitment of AP-2 (clathrin adapter protein complex 2), internalization through clathrin coated pits, and subsequent transport to endosomes and lysosomes for degradation. Diverts host MHC-I molecules to the trans-Golgi network-associated endosomal compartments by an endocytic pathway to finally target them for degradation. MHC-I down-regulation may involve AP-1 (clathrin adapter protein complex 1) or possibly Src family kinase-ZAP70/Syk-PI3K cascade recruited by PACS2. In consequence infected cells are masked for immune recognition by cytotoxic T-lymphocytes. Decreasing the number of immune receptors also prevents reinfection by more HIV particles (superinfection) (By similarity).[11] [12] [13] [14] [15] [16] Bypasses host T-cell signaling by inducing a transcriptional program nearly identical to that of anti-CD3 cell activation. Interaction with TCR-zeta chain up-regulates the Fas ligand (FasL). Increasing surface FasL molecules and decreasing surface MHC-I molecules on infected CD4(+) cells send attacking cytotoxic CD8+ T-lymphocytes into apoptosis (By similarity).[17] [18] [19] [20] [21] [22] Plays a role in optimizing the host cell environment for viral replication without causing cell death by apoptosis. Protects the infected cells from apoptosis in order to keep them alive until the next virus generation is ready to strike. Inhibits the Fas and TNFR-mediated death signals by blocking MAP3K5. Interacts and decreases the half-life of p53, protecting the infected cell against p53-mediated apoptosis. Inhibits the apoptotic signals regulated by the Bcl-2 family proteins through the formation of a Nef/PI3-kinase/PAK2 complex that leads to activation of PAK2 and induces phosphorylation of Bad (By similarity).[23] [24] [25] [26] [27] [28] Extracellular Nef protein targets CD4(+) T-lymphocytes for apoptosis by interacting with CXCR4 surface receptors (By similarity).[29] [30] [31] [32] [33] [34] [HCK_HUMAN] Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS.[35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53]
Publication Abstract from PubMed
Increased spread of HIV-1 and rapid emergence of drug resistance warrants development of novel antiviral strategies. Nef, a critical viral pathogenicity factor that interacts with host cell factors but lacks enzymatic activity, is not targeted by current antiviral measures. Here we inhibit Nef function by simultaneously blocking several highly conserved protein interaction surfaces. This strategy, referred to as "wrapping Nef", is based on structure-function analyses that led to the identification of four target sites: (i) SH3 domain interaction, (ii) interference with protein transport processes, (iii) CD4 binding and (iv) targeting to lipid membranes. Screening combinations of Nef-interacting domains, we developed a series of small Nef interacting proteins (NIs) composed of an SH3 domain optimized for binding to Nef, fused to a sequence motif of the CD4 cytoplasmic tail and combined with a prenylation signal for membrane association. NIs bind to Nef in the low nM affinity range, associate with Nef in human cells and specifically interfere with key biological activities of Nef. Structure determination of the Nef-inhibitor complex reveals the molecular basis for binding specificity. These results establish Nef-NI interfaces as promising leads for the development of potent Nef inhibitors.
Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.,Breuer S, Schievink SI, Schulte A, Blankenfeldt W, Fackler OT, Geyer M PLoS One. 2011;6(5):e20033. Epub 2011 May 20. PMID:21625496[54]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Poincloux R, Al Saati T, Maridonneau-Parini I, Le Cabec V. The oncogenic activity of the Src family kinase Hck requires the cooperative action of the plasma membrane- and lysosome-associated isoforms. Eur J Cancer. 2009 Feb;45(3):321-7. doi: 10.1016/j.ejca.2008.11.020. Epub 2008, Dec 26. PMID:19114024 doi:10.1016/j.ejca.2008.11.020
- ↑ Pene-Dumitrescu T, Smithgall TE. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J Biol Chem. 2010 Jul 9;285(28):21446-57. doi: 10.1074/jbc.M109.090043. Epub 2010, May 7. PMID:20452982 doi:10.1074/jbc.M109.090043
- ↑ Poincloux R, Al Saati T, Maridonneau-Parini I, Le Cabec V. The oncogenic activity of the Src family kinase Hck requires the cooperative action of the plasma membrane- and lysosome-associated isoforms. Eur J Cancer. 2009 Feb;45(3):321-7. doi: 10.1016/j.ejca.2008.11.020. Epub 2008, Dec 26. PMID:19114024 doi:10.1016/j.ejca.2008.11.020
- ↑ Pene-Dumitrescu T, Smithgall TE. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J Biol Chem. 2010 Jul 9;285(28):21446-57. doi: 10.1074/jbc.M109.090043. Epub 2010, May 7. PMID:20452982 doi:10.1074/jbc.M109.090043
- ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
- ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
- ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
- ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
- ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
- ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
- ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
- ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
- ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
- ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
- ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
- ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
- ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
- ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
- ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
- ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
- ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
- ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
- ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
- ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
- ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
- ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
- ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
- ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
- ↑ Briggs SD, Sharkey M, Stevenson M, Smithgall TE. SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. J Biol Chem. 1997 Jul 18;272(29):17899-902. PMID:9218412
- ↑ Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96. PMID:10224289
- ↑ Kim YH, Chang SH, Kwon JH, Rhee SS. HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. Virology. 1999 Apr 25;257(1):208-19. PMID:10208934 doi:S0042-6822(99)99642-3
- ↑ Arora VK, Molina RP, Foster JL, Blakemore JL, Chernoff J, Fredericksen BL, Garcia JV. Lentivirus Nef specifically activates Pak2. J Virol. 2000 Dec;74(23):11081-7. PMID:11070003
- ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
- ↑ Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24. PMID:11689886 doi:10.1038/nm1101-1217
- ↑ Ghazizadeh S, Bolen JB, Fleit HB. Physical and functional association of Src-related protein tyrosine kinases with Fc gamma RII in monocytic THP-1 cells. J Biol Chem. 1994 Mar 25;269(12):8878-84. PMID:8132624
- ↑ Durden DL, Kim HM, Calore B, Liu Y. The Fc gamma RI receptor signals through the activation of hck and MAP kinase. J Immunol. 1995 Apr 15;154(8):4039-47. PMID:7535819
- ↑ Hallek M, Neumann C, Schaffer M, Danhauser-Riedl S, von Bubnoff N, de Vos G, Druker BJ, Yasukawa K, Griffin JD, Emmerich B. Signal transduction of interleukin-6 involves tyrosine phosphorylation of multiple cytosolic proteins and activation of Src-family kinases Fyn, Hck, and Lyn in multiple myeloma cell lines. Exp Hematol. 1997 Dec;25(13):1367-77. PMID:9406996
- ↑ Warmuth M, Bergmann M, Priess A, Hauslmann K, Emmerich B, Hallek M. The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr. J Biol Chem. 1997 Dec 26;272(52):33260-70. PMID:9407116
- ↑ Howlett CJ, Bisson SA, Resek ME, Tigley AW, Robbins SM. The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein-tyrosine kinase. Biochem Biophys Res Commun. 1999 Apr 2;257(1):129-38. PMID:10092522 doi:10.1006/bbrc.1999.0427
- ↑ Bosco MC, Curiel RE, Zea AH, Malabarba MG, Ortaldo JR, Espinoza-Delgado I. IL-2 signaling in human monocytes involves the phosphorylation and activation of p59hck. J Immunol. 2000 May 1;164(9):4575-85. PMID:10779760
- ↑ Barlic J, Andrews JD, Kelvin AA, Bosinger SE, DeVries ME, Xu L, Dobransky T, Feldman RD, Ferguson SS, Kelvin DJ. Regulation of tyrosine kinase activation and granule release through beta-arrestin by CXCRI. Nat Immunol. 2000 Sep;1(3):227-33. PMID:10973280 doi:10.1038/79767
- ↑ Klejman A, Schreiner SJ, Nieborowska-Skorska M, Slupianek A, Wilson M, Smithgall TE, Skorski T. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J. 2002 Nov 1;21(21):5766-74. PMID:12411494
- ↑ Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR. Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases. J Biol Chem. 2002 Feb 15;277(7):4999-5007. Epub 2001 Dec 10. PMID:11741929 doi:10.1074/jbc.M107430200
- ↑ Carreno S, Caron E, Cougoule C, Emorine LJ, Maridonneau-Parini I. p59Hck isoform induces F-actin reorganization to form protrusions of the plasma membrane in a Cdc42- and Rac-dependent manner. J Biol Chem. 2002 Jun 7;277(23):21007-16. Epub 2002 Mar 19. PMID:11904303 doi:10.1074/jbc.M201212200
- ↑ Howlett CJ, Robbins SM. Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation. Oncogene. 2002 Mar 7;21(11):1707-16. PMID:11896602 doi:10.1038/sj.onc.1205228
- ↑ Podar K, Mostoslavsky G, Sattler M, Tai YT, Hayashi T, Catley LP, Hideshima T, Mulligan RC, Chauhan D, Anderson KC. Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells. J Biol Chem. 2004 May 14;279(20):21658-65. Epub 2004 Mar 9. PMID:15010462 doi:10.1074/jbc.M305783200
- ↑ Yokoyama N, deBakker CD, Zappacosta F, Huddleston MJ, Annan RS, Ravichandran KS, Miller WT. Identification of tyrosine residues on ELMO1 that are phosphorylated by the Src-family kinase Hck. Biochemistry. 2005 Jun 21;44(24):8841-9. PMID:15952790 doi:10.1021/bi0500832
- ↑ Cougoule C, Carreno S, Castandet J, Labrousse A, Astarie-Dequeker C, Poincloux R, Le Cabec V, Maridonneau-Parini I. Activation of the lysosome-associated p61Hck isoform triggers the biogenesis of podosomes. Traffic. 2005 Aug;6(8):682-94. PMID:15998323 doi:10.1111/j.1600-0854.2005.00307.x
- ↑ Paliwal P, Radha V, Swarup G. Regulation of p73 by Hck through kinase-dependent and independent mechanisms. BMC Mol Biol. 2007 May 30;8:45. PMID:17535448 doi:10.1186/1471-2199-8-45
- ↑ Hausherr A, Tavares R, Schaffer M, Obermeier A, Miksch C, Mitina O, Ellwart J, Hallek M, Krause G. Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases. Oncogene. 2007 Jul 26;26(34):4987-98. Epub 2007 Feb 19. PMID:17310994 doi:10.1038/sj.onc.1210306
- ↑ Poincloux R, Al Saati T, Maridonneau-Parini I, Le Cabec V. The oncogenic activity of the Src family kinase Hck requires the cooperative action of the plasma membrane- and lysosome-associated isoforms. Eur J Cancer. 2009 Feb;45(3):321-7. doi: 10.1016/j.ejca.2008.11.020. Epub 2008, Dec 26. PMID:19114024 doi:10.1016/j.ejca.2008.11.020
- ↑ Baruzzi A, Iacobucci I, Soverini S, Lowell CA, Martinelli G, Berton G. c-Abl and Src-family kinases cross-talk in regulation of myeloid cell migration. FEBS Lett. 2010 Jan 4;584(1):15-21. doi: 10.1016/j.febslet.2009.11.009. Epub . PMID:19903482 doi:10.1016/j.febslet.2009.11.009
- ↑ Pene-Dumitrescu T, Smithgall TE. Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. J Biol Chem. 2010 Jul 9;285(28):21446-57. doi: 10.1074/jbc.M109.090043. Epub 2010, May 7. PMID:20452982 doi:10.1074/jbc.M109.090043
- ↑ Breuer S, Schievink SI, Schulte A, Blankenfeldt W, Fackler OT, Geyer M. Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef. PLoS One. 2011;6(5):e20033. Epub 2011 May 20. PMID:21625496 doi:http://dx.doi.org/10.1371/journal.pone.0020033
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