Alt. symbols: JTK9

Approved name: HCK proto-oncogene, Src family tyrosine kinase
Alt. names: hemopoietic cell kinase

Location: 20q11.21: 32052197 - 32101856 (+)
Gene type: protein_coding, 8 transcripts.

Scores: LoFtool: 0.176000 | pLI: 0.01976000 | LOEUF: 0.510

HGNC: 4840

NCBI: 3055, RefSeq: NG_029471.1

Ensembl: ENSG00000101336.18

LRG_ | Status: none

OMIM: 142370

Expression | ProteinAtlas

HCK encodes hematopoietic cell kinase (HCK), a member of the SRC family of non-receptor tyrosine kinases (NRTKs). It is predominantly expressed in myeloid and B cell lineages and is implicated in phagocyte migration and degranulation, as well as receptor-mediated signaling (PMID: 12029088). However, these roles have mostly been elucidated using double and triple knockout mice for multiple SRC family NRTKs and the specific roles of each kinase have been difficult to dissect (PMID: 18385944). Hck is expressed as 2 isoforms - p59Hck is associated with the plasma membrane where it triggers the formation of protrusions and p61Hck is associated with lysosomal membranes that contribute to the formation of podosome rosettes (PMID: 19897576). Cougoule et al. (2010) showed that Hck-deficient macrophages have altered in vitro migration and in vivo tissue invasion capacities (PMID: 19897576). Moreover, Hck appears to play an important role in proliferative signaling downstream of IL-6/gp130 (PMID: 26087188). In B cell development, HCK is generally expressed in earlier B-cell progenitors and downregulated in mature B cells (PMID: 10658677). However, in MYD88-driven B-cell lymphomas (Waldenström macroglobulinemia and activated B-cell subtype diffuse large B-cell lymphomas) that represent later stages of B-cell differentiation, HCK is aberrantly overexpressed and triggers multiple growth and survival pathways (PMID: 31935288).

Kanderova et al. (2022) identified a heterozygous de novo HCK nonsense mutation (Y515X) in a female with early onset cutaneous vasculitis and chronic pulmonary inflammation progressing to fibrosis (PMID: 34536415). As a neonate, the patient develop petechial and purpuric skin lesions and was found to have vasculitis with perivascular neutrophil and macrophage infiltration. She then developed hepatosplenomegaly around 21 months of age and bilateral lung parenchymal infiltration with persistent ep isodes of alveolar hemorrhage. Though the patient’s clinical findings were responsive to ruxolitinib treatment, she developed recurrent infectious complications and eventually passed away from respiratory failure at age 17. the authors showed that the mutation led to a truncated protein lacking 12 amino acids, including loss of a key residue (Tyr522) that mediates intramolecular inhibition of kinase activity. Over-expression of the mutant allele in cell lines showed that it causes increased kinase activity with hyperphosphorylation in whole-cell lysates. The authors also showed that this hyperactive form of HCK led to increased integrin expression, chemotaxis, and migration as well as inflammatory cytokine production (IL-1β, IL-6, IL-8, TNF-alpha), likely accounting for the patient’s lung infiltration and inflammation. [Load More]