Alternative titles; symbols
HGNC Approved Gene Symbol: HCK
Cytogenetic location: 20q11.21 Genomic coordinates (GRCh38) : 20:32,052,242-32,101,856 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.21 | Autoinflammation with pulmonary and cutaneous vasculitis | 620296 | Autosomal dominant | 3 |
HCK is an SRC (190090) family tyrosine kinase that is expressed predominantly in granulocytic and monocytic cells. It has proposed functional roles in phagocytosis and receptor-mediated signaling (summary by Scott et al., 2002).
During a search for a cDNA clone representing human SRC, Quintrell et al. (1987) encountered a previously unrecognized gene that appeared to encode a protein-tyrosine kinase similar to SRC. Ziegler et al. (1987) found the same gene by a different route. Expression of this gene may be limited to certain hemopoietic cells and is especially prominent in cells of myeloid lineage, particularly mature granulocytes and monocytes. Therefore, Quintrell et al. (1987) designated the gene HCK (pronounced 'hick') for hemopoietic cell kinase. They described the nucleotide sequence of a cDNA clone representing most or all of the mRNA for HCK, the deduced amino acid sequence of the protein encoded by HCK, and the distribution of RNA transcribed from HCK among various hemopoietic cells. The deduced HCK protein contains 505 amino acids and has a calculated molecular mass of about 57 kD.
Using mass spectrometric analysis, Scott et al. (2002) identified 25 potential binding partners in a human monocyte cell line for the SH3 domain of HCK. Analysis with purified proteins and in intact cells confirmed the interactions with WIP (WIPF1; 602357), WASP (WAS; 300392), and ELMO1 (606420). ELMO1 was heavily tyrosine phosphorylated in cells coexpressing HCK and ELMO1, suggesting that ELMO1 is a HCK substrate. Pull-down analysis showed that binding of ELMO1 to the HCK SH3 domain could be inhibited by polyproline peptides, indicating that an ELMO1 polyproline motif interacts with HCK. Scott et al. (2002) concluded that WIP, WASP, and ELMO1 may be activators or effectors of HCK.
Kanderova et al. (2022) summarized how HCK function is controlled by phosphorylation of 2 important tyrosines. The activating tyrosine, tyr411, is located within the kinase domain, and its autophosphorylation enhances kinase activity. The inhibitory tyrosine, tyr522, is located in the C-terminal tail; upon phosphorylation it interacts with the SH2 domain of the same molecule, and this intramolecular interaction inhibits kinase activity.
By spot-blot analysis of sorted chromosomes and by in situ hybridization, Quintrell et al. (1987) assigned the HCK gene to chromosome 20q11-q12. Since this region is affected by interstitial deletions in some acute myeloid leukemias and myeloproliferative disorders, they suggested that damage to HCK may contribute to the pathogenesis of these conditions.
In a 17-year-old girl with autoinflammation with pulmonary and cutaneous vasculitis (AIPCV; 620296), Kanderova et al. (2022) identified a de novo heterozygous nonsense mutation in the HCK gene (Y515X; 142370.0001) that was predicted to produce a truncated protein lacking 12 amino acids in the C terminus, including the inhibitory residue tyr522. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional studies of patient immune cells and immune cell lines showed that the mutation caused a gain-of-function effect with increased HCK kinase activity and a hyperinflammatory effect.
In a 17-year-old girl with autoinflammation with pulmonary and cutaneous vasculitis (AIPCV; 620296), Kanderova et al. (2022) identified a de novo heterozygous c.1545C-A transversion in the HCK gene, resulting in a tyr515-to-ter (Y515X) substitution that was predicted to produce a truncated protein lacking 12 amino acids in the C terminus, including the inhibitory residue tyr522. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient peripheral blood cells expressed both the wildtype and mutated protein, although overall HCK expression was decreased compared to controls. Patient cells and cell lines expressing the Y515X mutation showed increased kinase activity and increased phosphorylation of the activating tyrosine tyr411 compared to controls, indicating a gain-of-function effect. Further in vitro studies showed that presence of the mutant protein increased inflammatory signaling in immune cells manifest by expression of markers of activation, hyperproduction of reactive oxygen species (in neutrophils), induction of chemotaxis, and enhanced cytokine production. The findings were consistent with immune dysregulation and chronic inflammation of the skin and lungs found in the patient. Although treatment with the JAK inhibitor ruxolitinib partially suppressed the inflammation, the patient died of complications of the disease.
Kanderova, V., Svobodova, T., Borna, S., Fejtkova, M., Martinu, V., Paderova, J., Svaton, M., Kralova, J., Fronkova, E., Klocperk, A., Pruhova, S., Lee-Kirsch, M. A., and 18 others. Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK. J. Allergy Clin. Immun. 149: 1464-1472, 2022. [PubMed: 34536415] [Full Text: https://doi.org/10.1016/j.jaci.2021.07.046]
Quintrell, N., Lebo, R., Varmus, H., Bishop, J. M., Pettenati, M. J., Le Beau, M. M., Diaz, M. O., Rowley, J. D. Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells. Molec. Cell. Biol. 7: 2267-2275, 1987. [PubMed: 3496523] [Full Text: https://doi.org/10.1128/mcb.7.6.2267-2275.1987]
Scott, M. P., Zappacosta, F., Kim, E. Y., Annan, R. S., Miller, W. T. Identification of novel SH3 domain ligands for the Src family kinase Hck: Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and ELMO1. J. Biol. Chem. 277: 28238-28246, 2002. [PubMed: 12029088] [Full Text: https://doi.org/10.1074/jbc.M202783200]
Ziegler, S. F., Marth, J. D., Lewis, D. B., Perlmutter, R. M. Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin. Molec. Cell. Biol. 7: 2276-2285, 1987. [PubMed: 3453117] [Full Text: https://doi.org/10.1128/mcb.7.6.2276-2285.1987]