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Hck  -  hemopoietic cell kinase

Mus musculus

Synonyms: AI849071, B-cell/myeloid kinase, BMK, Bmk, Hck-1, ...
 
 
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Disease relevance of Hck

  • Here, in a model of thrombohemorrhagic vasculitis, the CD18 integrin Mac-1 on neutrophils recognized complement C3 deposited within vessel walls and triggered a signaling pathway involving the Src-family kinase Hck and the Syk tyrosine kinase [1].
  • Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response [2].
  • Unlike their Hck(-/-) "loss-of-function" counterparts, Hck(F/F) "gain-of-function" mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways [2].
  • Resistance to endotoxic shock and reduced neutrophil migration in mice deficient for the Src-family kinases Hck and Fgr [3].
  • Both tissue and airway eosinophilia were markedly reduced in fgr(-/-) mice, whereas mice with the sole deficiency of Hck, another Src family member, responded normally [4].
 

High impact information on Hck

  • Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases [5].
  • The specific activity of the Lyn protein kinase is increased in hck-l- macrophages, implying that Lyn may compensate for a deficiency in Hck [6].
  • The Src family kinases Hck and Fgr negatively regulate neutrophil and dendritic cell chemokine signaling via PIR-B [7].
  • To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) "knock-in" mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(499)-residue in the Hck protein [2].
  • Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes [2].
 

Biological context of Hck

 

Anatomical context of Hck

  • Expression of the Src-family kinases--Src, Hck, and Fgr--increases dramatically during myeloid cell development [10].
  • These observations suggest that Hck and Src serve partially overlapping functions in osteoclasts and that the expression of Hck in src-/- osteoclasts ameliorates their functional defects [10].
  • Mice genetically deficient in any of these components (C3, Mac-1, Hck, Syk, or elastase) were resistant to disease despite normal tissue neutrophil accumulation [1].
  • We found that mouse erythrocytes express the Src-family kinases Fgr and Hck, as well as Lyn [12].
  • Hck-mediated cellular transformation of murine fibroblasts is reverted by ectopic expression of a membrane-anchored allele of Cbl as assessed by the cellular morphology, suppression of anchorage independent growth, and an overall reduction in the total tyrosine phosphorylation levels within the cells [13].
 

Associations of Hck with chemical compounds

  • Recently, an increasing amount of evidence suggests that protein tyrosine kinases especially the Src-family kinases Hck, Fgr, and Lyn, play important roles in LPS signaling [8].
  • These data provide biochemical and morphological evidence that the Src-family kinases Hck and Fgr are required for normal integrin-mediated signal transduction in murine macrophages [14].
  • The inability of Hck to bind the phosphopeptide was not a result of a stable intramolecular interaction between its SH2 domain and C-terminal regulatory phosphotyrosine residue (Tyr-520), as most Hck molecules in the purified Hck preparation were not tyrosine-phosphorylated [15].
  • We have found that upon enzymatic activation of Hck by the heavy metal mercuric chloride, there was a rapid increase in the levels of tyrosine phosphorylation of several proteins including the proto-oncogene p120(Cbl) [16].
  • Using a novel estrogen-regulated chimera of Hck we have shown a hormone-dependent association between Hck and Cbl in murine fibroblasts [16].
 

Physical interactions of Hck

 

Regulatory relationships of Hck

  • Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation [13].
 

Other interactions of Hck

  • Differentiation of ES cells to embryoid bodies was associated with rapid transcriptional silencing of Hck and Lck and with the loss of the corresponding kinase proteins [18].
  • In this article, we show that murine ES cells express seven SFKs, three of which (Hck, Src, and Fyn) exhibit constitutive activity in self-renewing ES cells [18].
  • This was not the case for the SH2 domain of Hck, however, as binding of the Hck fusion protein to Cbl appeared to require multiple domains [19].
  • Additionally, examination of integrin affinity by soluble ICAM-1 binding assays and of beta(2) integrin clustering on the cell surface, showed that integrin activation did not require Hck and Fgr expression [20].
  • Tyrosine phosphorylation of hematopoeitic cell kinase (Hck), a Src found in macrophages, was detectable within 1 to 5 min after DON addition, and this was suppressed by PP1 [21].
 

Analytical, diagnostic and therapeutic context of Hck

  • RESULTS: In acutely rejecting allografts from untreated controls, total activity of Hck and Lyn increased 10-fold, predominantly reflecting increases in the amount of protein [22].

References

  1. Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Hirahashi, J., Mekala, D., Van Ziffle, J., Xiao, L., Saffaripour, S., Wagner, D.D., Shapiro, S.D., Lowell, C., Mayadas, T.N. Immunity (2006) [Pubmed]
  2. Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response. Ernst, M., Inglese, M., Scholz, G.M., Harder, K.W., Clay, F.J., Bozinovski, S., Waring, P., Darwiche, R., Kay, T., Sly, P., Collins, R., Turner, D., Hibbs, M.L., Anderson, G.P., Dunn, A.R. J. Exp. Med. (2002) [Pubmed]
  3. Resistance to endotoxic shock and reduced neutrophil migration in mice deficient for the Src-family kinases Hck and Fgr. Lowell, C.A., Berton, G. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Fgr deficiency results in defective eosinophil recruitment to the lung during allergic airway inflammation. Vicentini, L., Mazzi, P., Caveggion, E., Continolo, S., Fumagalli, L., Lapinet-Vera, J.A., Lowell, C.A., Berton, G. J. Immunol. (2002) [Pubmed]
  5. Src tyrosine kinase is a novel direct effector of G proteins. Ma, Y.C., Huang, J., Ali, S., Lowry, W., Huang, X.Y. Cell (2000) [Pubmed]
  6. Functional overlap in the src gene family: inactivation of hck and fgr impairs natural immunity. Lowell, C.A., Soriano, P., Varmus, H.E. Genes Dev. (1994) [Pubmed]
  7. The Src family kinases Hck and Fgr negatively regulate neutrophil and dendritic cell chemokine signaling via PIR-B. Zhang, H., Meng, F., Chu, C.L., Takai, T., Lowell, C.A. Immunity (2005) [Pubmed]
  8. Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn. Meng, F., Lowell, C.A. J. Exp. Med. (1997) [Pubmed]
  9. Fcgamma receptor-mediated phagocytosis in macrophages lacking the Src family tyrosine kinases Hck, Fgr, and Lyn. Fitzer-Attas, C.J., Lowry, M., Crowley, M.T., Finn, A.J., Meng, F., DeFranco, A.L., Lowell, C.A. J. Exp. Med. (2000) [Pubmed]
  10. Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis. Lowell, C.A., Niwa, M., Soriano, P., Varmus, H.E. Blood (1996) [Pubmed]
  11. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Golas, J.M., Arndt, K., Etienne, C., Lucas, J., Nardin, D., Gibbons, J., Frost, P., Ye, F., Boschelli, D.H., Boschelli, F. Cancer Res. (2003) [Pubmed]
  12. Deficiency of Src family kinases Fgr and Hck results in activation of erythrocyte K/Cl cotransport. De Franceschi, L., Fumagalli, L., Olivieri, O., Corrocher, R., Lowell, C.A., Berton, G. J. Clin. Invest. (1997) [Pubmed]
  13. Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation. Howlett, C.J., Robbins, S.M. Oncogene (2002) [Pubmed]
  14. Impaired integrin-mediated signal transduction, altered cytoskeletal structure and reduced motility in Hck/Fgr deficient macrophages. Suen, P.W., Ilic, D., Caveggion, E., Berton, G., Damsky, C.H., Lowell, C.A. J. Cell. Sci. (1999) [Pubmed]
  15. Common in vitro substrate specificity and differential Src homology 2 domain accessibility displayed by two members of the Src family of protein-tyrosine kinases, c-Src and Hck. Sicilia, R.J., Hibbs, M.L., Bello, P.A., Bjorge, J.D., Fujita, D.J., Stanley, I.J., Dunn, A.R., Cheng, H.C. J. Biol. Chem. (1998) [Pubmed]
  16. The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein-tyrosine kinase. Howlett, C.J., Bisson, S.A., Resek, M.E., Tigley, A.W., Robbins, S.M. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  17. CpG DNA enhances macrophage cell spreading by promoting the Src-family kinase-mediated phosphorylation of paxillin. Achuthan, A., Elsegood, C., Masendycz, P., Hamilton, J.A., Scholz, G.M. Cell. Signal. (2006) [Pubmed]
  18. SRC family kinase activity is required for murine embryonic stem cell growth and differentiation. Meyn, M.A., Schreiner, S.J., Dumitrescu, T.P., Nau, G.J., Smithgall, T.E. Mol. Pharmacol. (2005) [Pubmed]
  19. Phosphorylation of Cbl following stimulation with interleukin-3 and its association with Grb2, Fyn, and phosphatidylinositol 3-kinase. Anderson, S.M., Burton, E.A., Koch, B.L. J. Biol. Chem. (1997) [Pubmed]
  20. The Src family kinases Hck and Fgr are dispensable for inside-out, chemoattractant-induced signaling regulating beta 2 integrin affinity and valency in neutrophils, but are required for beta 2 integrin-mediated outside-in signaling involved in sustained adhesion. Giagulli, C., Ottoboni, L., Caveggion, E., Rossi, B., Lowell, C., Constantin, G., Laudanna, C., Berton, G. J. Immunol. (2006) [Pubmed]
  21. Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. Zhou, H.R., Jia, Q., Pestka, J.J. Toxicol. Sci. (2005) [Pubmed]
  22. Inhibition of Src kinases combined with CD40 ligand blockade prolongs murine cardiac allograft survival. Zhang, Q., Fairchild, R.L., Reich, M.B., Miller, G.G. Transplantation (2005) [Pubmed]
 
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