HCK

For other uses, see HCK (disambiguation).

Tyrosine-protein kinase HCK is an enzyme that in humans is encoded by the HCK gene.

HCK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1AD5, 1BU1, 1QCF, 2C0I, 2C0O, 2C0T, 2HCK, 2HK5, 2OI3, 2OJ2, 3HCK, 3NHN, 3RBB, 3REA, 3REB, 3VRY, 3VRZ, 3VS0, 3VS1, 3VS2, 3VS3, 3VS4, 3VS5, 3VS6, 3VS7, 4HCK, 4LUD, 4LUE, 4ORZ, 4U5W, 5HCK
Identifiers
Aliases	HCK, JTK9, p59Hck, p61Hck, HCK proto-oncogene, Src family tyrosine kinase
External IDs	OMIM: 142370; MGI: 96052; HomoloGene: 20489; GeneCards: HCK; OMA:HCK - orthologs
Gene location (Human) Chr. Chromosome 20 (human) Band 20q11.21 Start 32,052,197 bp End 32,101,856 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2 H1|2 75.41 cM Start 152,950,388 bp End 152,993,361 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte blood spleen bone marrow appendix trabecular bone middle frontal gyrus bone marrow cells periodontal fiber Top expressed in granulocyte stroma of bone marrow tibiofemoral joint spleen blood rib mesenteric lymph nodes right lung lobe transitional epithelium of urinary bladder left lung More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity non-membrane spanning protein tyrosine kinase activity kinase activity protein binding signaling receptor binding ATP binding protein tyrosine kinase activity phosphotyrosine residue binding Cellular component cytoplasm cytosol Golgi apparatus cell projection membrane focal adhesion extrinsic component of cytoplasmic side of plasma membrane transport vesicle cell junction actin filament caveola lysosome cytoskeleton cytoplasmic vesicle nucleus nucleoplasm plasma membrane Biological process cell differentiation leukocyte migration involved in immune response positive regulation of actin filament polymerization Fc-gamma receptor signaling pathway involved in phagocytosis phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway cytokine-mediated signaling pathway interferon-gamma-mediated signaling pathway immune system process leukocyte degranulation negative regulation of apoptotic process mitigation of host defenses by virus protein phosphorylation cell adhesion respiratory burst after phagocytosis regulation of DNA-binding transcription factor activity positive regulation of cell population proliferation regulation of inflammatory response regulation of cell shape regulation of podosome assembly peptidyl-tyrosine autophosphorylation phagocytosis integrin-mediated signaling pathway protein autophosphorylation peptidyl-tyrosine phosphorylation regulation of phagocytosis mesoderm development inflammatory response innate immune response-activating signal transduction positive regulation of actin cytoskeleton reorganization lipopolysaccharide-mediated signaling pathway exocytosis viral process innate immune response Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3055 15162 Ensembl ENSG00000101336 ENSMUSG00000003283 UniProt P08631 P08103 RefSeq (mRNA) NM_002110 NM_001172129 NM_001172130 NM_001172131 NM_001172132 NM_001172133 NM_001172117 NM_010407 RefSeq (protein) NP_001165600 NP_001165601 NP_001165602 NP_001165603 NP_001165604 NP_002101 NP_001165588 NP_034537 Location (UCSC) Chr 20: 32.05 – 32.1 Mb Chr 2: 152.95 – 152.99 Mb PubMed search
Wikidata
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Structure

HCK comprises five distinct domains which include two terminal domains and three SH domains. The N-terminal domain is important for lipid modifications and a C-terminal domain includes a regulatory tyrosine residue. Next, HCK comprises three highly conserved SH domains: SH1, SH2, and SH3. The catalytic SH1 domain houses the kinase's active site. The regulatory SH3 and SH2 domains are tightly bound together when HCK is in an inactive state.

Signaling

HCK is localized in the cytoplasm where it executes its functions as a kinase.  In a steady state, HCK remains in an inactive conformation. Upon interaction with stimuli, such as TLR4 or IL-2, C-terminal tyrosine residues of HCK are dephosphorylated by phosphatases, e.g. CD45, and the inactive conformation of HCK is disrupted resulting in HCK activation. Activated HCK can then phosphorylate downstream molecules such as Bcr/Abl, PI3K/AKT, MAPK/ERK or STAT5 which then participate in myeloid cell polarization, proliferation and migration. A case study of a patient with a loss of C-terminal tyrosine residue in HCK showed that the patient suffered from severe pneumonia and vasculitis. This was due to increased HCK activity which led to increased myeloid cell migration and effector functions, such as the production of pro-inflammatory cytokines IL1b, IL-6, IL-8, and TNF-a, and the production of reactive oxygen species. These abnormal functions manifested as the infiltration of inflammatory leukocytes into the lungs and skin, resulting in pneumonia and vasculitis.

Function

HCK plays a key role during inflammation as it participates in actin-dependent processes like phagocytosis, membrane remodeling, and cell migration. It has also been shown that HCK participates in NLRP3 inflammasome formation and LPS-induced inflammatory response in mice. However, the mechanism of action is yet to be elucidated. HCK not only participates in inflammation-associated processes but also in cancerous processes. It has been shown, that HCK is part of a CXCL12/CXCR4 signaling axis that is partially responsible for the migration of leukemic cells in the bone marrow of patients with acute myeloid leukemia. This finding proposes HCK to be a novel target for the treatment of acute myeloid leukemia. HCK and the Src family kinases have also been implicated in driving cell survival in drug-tolerant cancer cells.

Interactions

HCK has been shown to interact with:

• ADAM15
• BCR gene,
• Cbl gene,
• ELMO1,
• Granulocyte colony-stimulating factor receptor,
• RAPGEF1,
• RAS p21 protein activator 1, and
• RASA3.

Further reading

• Geyer M, Fackler OT, Peterlin BM (2001). "Structure--function relationships in HIV-1 Nef". EMBO Rep. 2 (7): 580–5. doi:10.1093/embo-reports/kve141. PMC 1083955. PMID 11463741.
• Lake JA, Carr J, Feng F, Mundy L, Burrell C, Li P (2003). "The role of Vif during HIV-1 infection: interaction with novel host cellular factors". J. Clin. Virol. 26 (2): 143–52. doi:10.1016/S1386-6532(02)00113-0. PMID 12600646.
• Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M (2004). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". J. Biosci. 28 (3): 323–35. doi:10.1007/BF02970151. PMID 12734410. S2CID 33749514.
• Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178.
• Joseph AM, Kumar M, Mitra D (2005). "Nef: "necessary and enforcing factor" in HIV infection". Curr. HIV Res. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
• Stove V, Verhasselt B (2006). "Modelling thymic HIV-1 Nef effects". Curr. HIV Res. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID 16454711.
• Lichtenberg U, Quintrell N, Bishop JM (1992). "Human protein-tyrosine kinase gene HCK: expression and structural analysis of the promoter region". Oncogene. 7 (5): 849–58. PMID 1373873.
• Hradetzky D, Strebhardt K, Rübsamen-Waigmann H (1992). "The genomic locus of the human hemopoietic-specific cell protein tyrosine kinase (PTK)-encoding gene (HCK) confirms conservation of exon-intron structure among human PTKs of the src family". Gene. 113 (2): 275–80. doi:10.1016/0378-1119(92)90407-G. PMID 1572549.
• Kim JW, Sim SS, Kim UH, Nishibe S, Wahl MI, Carpenter G, Rhee SG (1990). "Tyrosine residues in bovine phospholipase C-gamma phosphorylated by the epidermal growth factor receptor in vitro". J. Biol. Chem. 265 (7): 3940–3. doi:10.1016/S0021-9258(19)39684-X. PMID 1689310.
• Holtrich U, Bräuninger A, Strebhardt K, Rübsamen-Waigmann H (1992). "Two additional protein-tyrosine kinases expressed in human lung: fourth member of the fibroblast growth factor receptor family and an intracellular protein-tyrosine kinase". Proc. Natl. Acad. Sci. U.S.A. 88 (23): 10411–5. doi:10.1073/pnas.88.23.10411. PMC 52938. PMID 1720539.
• Lock P, Ralph S, Stanley E, Boulet I, Ramsay R, Dunn AR (1991). "Two isoforms of murine hck, generated by utilization of alternative translational initiation codons, exhibit different patterns of subcellular localization". Mol. Cell. Biol. 11 (9): 4363–70. doi:10.1128/mcb.11.9.4363. PMC 361298. PMID 1875927.
• Ziegler SF, Marth JD, Lewis DB, Perlmutter RM (1987). "Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin". Mol. Cell. Biol. 7 (6): 2276–85. doi:10.1128/mcb.7.6.2276. PMC 365352. PMID 3453117.
• Lee CH, Leung B, Lemmon MA, Zheng J, Cowburn D, Kuriyan J, Saksela K (1995). "A single amino acid in the SH3 domain of Hck determines its high affinity and specificity in binding to HIV-1 Nef protein". EMBO J. 14 (20): 5006–15. doi:10.1002/j.1460-2075.1995.tb00183.x. PMC 394604. PMID 7588629.
• Liao F, Shin HS, Rhee SG (1993). "In vitro tyrosine phosphorylation of PLC-gamma 1 and PLC-gamma 2 by src-family protein tyrosine kinases". Biochem. Biophys. Res. Commun. (Submitted manuscript). 191 (3): 1028–33. doi:10.1006/bbrc.1993.1320. PMID 7682059.
• Briggs SD, Bryant SS, Jove R, Sanderson SD, Smithgall TE (1995). "The Ras GTPase-activating protein (GAP) is an SH3 domain-binding protein and substrate for the Src-related tyrosine kinase, Hck". J. Biol. Chem. 270 (24): 14718–24. doi:10.1074/jbc.270.24.14718. PMID 7782336.
• Robbins SM, Quintrell NA, Bishop JM (1995). "Myristoylation and differential palmitoylation of the HCK protein-tyrosine kinases govern their attachment to membranes and association with caveolae". Mol. Cell. Biol. 15 (7): 3507–15. doi:10.1128/mcb.15.7.3507. PMC 230587. PMID 7791757.
• Saksela K, Cheng G, Baltimore D (1995). "Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down-regulation of CD4". EMBO J. 14 (3): 484–91. doi:10.1002/j.1460-2075.1995.tb07024.x. PMC 398106. PMID 7859737.
• Cheng G, Ye ZS, Baltimore D (1994). "Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction". Proc. Natl. Acad. Sci. U.S.A. 91 (17): 8152–5. Bibcode:1994PNAS...91.8152C. doi:10.1073/pnas.91.17.8152. PMC 44563. PMID 8058772.
• Wang AV, Scholl PR, Geha RS (1994). "Physical and functional association of the high affinity immunoglobulin G receptor (Fc gamma RI) with the kinases Hck and Lyn". J. Exp. Med. 180 (3): 1165–70. doi:10.1084/jem.180.3.1165. PMC 2191633. PMID 8064233.