| 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
[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.[5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]
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
Most mammalian cell types depend on multiple Src-family kinases (SFKs) to regulate diverse signaling pathways. Strict control of SFK activity is essential to normal cellular function and loss of kinase regulation contributes to several forms of cancer and other diseases. Previous X-ray crystal structures of the SFKs c-Src and Hck revealed that intramolecular association of their SH3 domains and SH2-kinase linker regions has a key role in downregulation of kinase activity. However, the amino acid sequence of the Hck linker represents a suboptimal ligand for the isolated SH3 domain, suggesting that it may form the PPII helical conformation required for SH3 docking only in the context of the intact structure. To test this hypothesis directly, we determined the crystal structure of a truncated Hck protein consisting of the SH2 and SH3 domains plus the linker. Despite the absence of the kinase domain, the structures and relative orientations of the SH2 and SH3 domains in this shorter protein were very similar to those observed in near-full-length, downregulated Hck. However, the SH2-kinase linker adopted a modified topology and failed to engage the SH3 domain. This new structure supports the idea that these non-catalytic regions work together as a conformational switch that modulates kinase activity in a manner unique to the SH3 domain and linker topologies present in the intact Hck protein. Our results also provide fresh structural insight into the facile induction of Hck activity by HIV-1 Nef and other Hck SH3-domain binding proteins, and implicate the existence of innate conformational states unique to individual Src-family members that fine-tune their sensitivities to activation by SH3-based ligands.
Crystal structure of the Src-family kinase Hck SH3-SH2-linker regulatory region supports an SH3-dominant activation mechanism.,Alvarado JJ, Betts L, Moroco JA, Smithgall TE, Yeh JI J Biol Chem. 2010 Sep 1. PMID:20810664[24]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ 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
- ↑ Alvarado JJ, Betts L, Moroco JA, Smithgall TE, Yeh JI. Crystal structure of the Src-family kinase Hck SH3-SH2-linker regulatory region supports an SH3-dominant activation mechanism. J Biol Chem. 2010 Sep 1. PMID:20810664 doi:10.1074/jbc.M110.145102
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