Biology:HCK

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Short description: Protein-coding gene in humans

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Tyrosine-protein kinase HCK is an enzyme that in humans is encoded by the HCK gene.[1]

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.[2][3][4]

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,[5][6] 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.[7] 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.[8][9][10] 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.[11]

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.[12] 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.[10] HCK and the Src family kinases have also been implicated in driving cell survival in drug-tolerant cancer cells.[13]

Interactions

HCK has been shown to interact with:

References

  1. ↑ "Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells". Molecular and Cellular Biology 7 (6): 2267–2275. June 1987. doi:10.1128/mcb.7.6.2267. PMID 3496523. 
  2. ↑ "Insights on hematopoietic cell kinase: An oncogenic player in human cancer". Biomedicine & Pharmacotherapy 160. April 2023. doi:10.1016/j.biopha.2023.114339. PMID 36736283. 
  3. ↑ "Crystal structure of the Src family tyrosine kinase Hck". Nature 385 (6617): 602–609. February 1997. doi:10.1038/385602a0. PMID 9024658. Bibcode: 1997Natur.385..602S. 
  4. ↑ "Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation". Cell 105 (1): 115–126. April 2001. doi:10.1016/S0092-8674(01)00301-4. PMID 11301007. 
  5. ↑ "IL-2 signaling in human monocytes involves the phosphorylation and activation of p59hck". Journal of Immunology 164 (9): 4575–4585. May 2000. doi:10.4049/jimmunol.164.9.4575. PMID 10779760. 
  6. ↑ "Hck tyrosine kinase regulates TLR4-induced TNF and IL-6 production via AP-1". Journal of Immunology 187 (11): 6043–6051. December 2011. doi:10.4049/jimmunol.1100967. PMID 22021612. 
  7. ↑ "A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45". Molecular Cell 67 (3): 498–511.e6. August 2017. doi:10.1016/j.molcel.2017.06.024. PMID 28735895. 
  8. ↑ "The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells". The EMBO Journal 21 (21): 5766–5774. November 2002. doi:10.1093/emboj/cdf562. PMID 12411494. 
  9. ↑ "The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains". Leukemia 17 (2): 283–289. February 2003. doi:10.1038/sj.leu.2402778. PMID 12592324. 
  10. ↑ 10.0 10.1 "Hematopoietic Cell Kinase (HCK) Is a Player of the Crosstalk Between Hematopoietic Cells and Bone Marrow Niche Through CXCL12/CXCR4 Axis". Frontiers in Cell and Developmental Biology 9. 2021-03-25. doi:10.3389/fcell.2021.634044. PMID 33842460. 
  11. ↑ "Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK". The Journal of Allergy and Clinical Immunology 149 (4): 1464–1472.e3. April 2022. doi:10.1016/j.jaci.2021.07.046. PMID 34536415. 
  12. ↑ "Hematopoietic Cell Kinase (HCK) Is Essential for NLRP3 Inflammasome Activation and Lipopolysaccharide-Induced Inflammatory Response In Vivo". Frontiers in Pharmacology 11. 2020-09-15. doi:10.3389/fphar.2020.581011. PMID 33041826. 
  13. ↑ "Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer". Nanophotonics 10 (12): 3063–3073. September 2021. doi:10.1515/nanoph-2021-0142. PMID 34589378. Bibcode: 2021Nanop..10..142S. 
  14. ↑ "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". The Journal of Biological Chemistry 277 (7): 4999–5007. February 2002. doi:10.1074/jbc.M107430200. PMID 11741929. 
  15. ↑ "The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains". Leukemia 17 (2): 283–289. February 2003. doi:10.1038/sj.leu.2402778. PMID 12592324. 
  16. ↑ "Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck". The Journal of Biological Chemistry 275 (24): 18581–18585. June 2000. doi:10.1074/jbc.C000126200. PMID 10849448. 
  17. ↑ "Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation". Oncogene 21 (11): 1707–1716. March 2002. doi:10.1038/sj.onc.1205228. PMID 11896602. 
  18. ↑ "The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein-tyrosine kinase". Biochemical and Biophysical Research Communications 257 (1): 129–138. April 1999. doi:10.1006/bbrc.1999.0427. PMID 10092522. 
  19. ↑ "Identification of novel SH3 domain ligands for the Src family kinase Hck. Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and ELMO1". The Journal of Biological Chemistry 277 (31): 28238–28246. August 2002. doi:10.1074/jbc.M202783200. PMID 12029088. 
  20. ↑ "The Src-like tyrosine kinase Hck is activated by granulocyte colony-stimulating factor (G-CSF) and docks to the activated G-CSF receptor". Biochemical and Biophysical Research Communications 251 (1): 117–123. October 1998. doi:10.1006/bbrc.1998.9441. PMID 9790917. Bibcode: 1998BBRC..251..117W. 
  21. ↑ "Physical and functional interaction between Hck tyrosine kinase and guanine nucleotide exchange factor C3G results in apoptosis, which is independent of C3G catalytic domain". The Journal of Biological Chemistry 278 (52): 52188–52194. December 2003. doi:10.1074/jbc.M310656200. PMID 14551197. 
  22. ↑ 22.0 22.1 "The Ras GTPase-activating protein (GAP) is an SH3 domain-binding protein and substrate for the Src-related tyrosine kinase, Hck". The Journal of Biological Chemistry 270 (24): 14718–14724. June 1995. doi:10.1074/jbc.270.24.14718. PMID 7782336. 

Further reading



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