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

• The current study provides direct evidence that three Src-family kinases Hck, Fgr, and Lyn are not obligatory for LPS-initiated signal transduction [8].
• Fcgamma receptor-mediated phagocytosis in macrophages lacking the Src family tyrosine kinases Hck, Fgr, and Lyn [9].
• Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn [8].
• Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis [10].
• Phosphorylation of the autoactivation site of the Src family kinases Lyn and/or Hck is also reduced by treatment with SKI-606 [11].

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

• Interestingly, both constitutively active and kinase-inactive Hck interact with and are targeted for degradation by Cbl [13].
• Furthermore, phosphorylation of paxillin by Hck created a binding site for Crk [17].

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