# HCK

## Overview
HCK, or Hematopoietic Cell Kinase, is a gene that encodes a member of the Src family of tyrosine kinases, specifically the HCK proto-oncogene, Src family tyrosine kinase. This protein is predominantly expressed in hematopoietic cells, such as monocytes, macrophages, and granulocytes, where it plays a pivotal role in various cellular processes, including signal transduction, phagocytosis, and cell migration. As a kinase, HCK is involved in the phosphorylation of tyrosine residues on target proteins, which is crucial for the regulation of immune responses and cellular communication. The protein's structure includes several domains, such as SH3, SH2, and a kinase domain, which facilitate its interactions with other proteins and its regulatory functions. HCK's activity is tightly controlled through phosphorylation and dephosphorylation events, and its dysregulation has been implicated in several hematological malignancies and solid tumors, highlighting its significance in both normal physiology and disease states (Guiet2008Hematopoietic; Engen2008Structure; Li2021HCK).

## Structure
HCK, a member of the Src family kinases, has a modular structure comprising several distinct domains. The protein includes an N-terminal myristoylation signal sequence, a unique domain, SH3 and SH2 domains, a regulatory linker, a kinase domain (SH1), and a C-terminal negative regulatory tail (Engen2008Structure). The SH3 domain binds to proline-rich sequences, while the SH2 domain interacts with phosphotyrosine-containing sequences, contributing to the negative regulation of kinase activity (Engen2008Structure). The kinase domain contains an activation loop with a critical tyrosine residue (Tyr-416) that is autophosphorylated to stabilize the active conformation (Engen2008Structure). The C-terminal tail contains another tyrosine (Tyr-527) that, when phosphorylated, interacts with the SH2 domain to maintain the kinase in an inactive state (Engen2008Structure).

HCK undergoes post-translational modifications, such as phosphorylation, which regulate its activity. The phosphorylation of Tyr-527 by regulatory kinases like Csk leads to downregulation of kinase activity through SH2:tail interactions (Engen2008Structure). The protein may exist in different isoforms due to alternative splicing, which can affect its functional properties (Perlmutter1989Specialized).

## Function
HCK, a member of the Src family of tyrosine kinases, is primarily expressed in hematopoietic cells, including myeloid cells such as monocytes, macrophages, and granulocytes. It plays a significant role in various cellular processes, particularly in the immune system. HCK is involved in integrin-mediated signal transduction in macrophages, which is crucial for phagocytosis and cell migration. It interacts with proteins like ELMO1, part of the CrkII/Dock180/Rac pathway, to facilitate these processes (Scott2002Identification).

HCK exists in two isoforms, p59Hck and p61Hck, which have distinct subcellular localizations and functions. These isoforms are involved in phagocytosis, adhesion, migration, and actin polymerization. p59Hck is associated with the plasma membrane, while p61Hck is linked to lysosomes, indicating their roles in different cellular compartments (Guiet2008Hematopoietic).

In healthy cells, HCK is activated by phosphorylation and dephosphorylation events, which are modulated by specific kinases and phosphatases. This regulation is essential for its role in immune responses, including lysosome fusion with phagosomes in neutrophils, a critical step in phagocytosis (Guiet2008Hematopoietic). HCK's activity is also linked to the production of inflammatory molecules, such as tumor necrosis factor (TNF), in response to stimuli like lipopolysaccharide (LPS) (English1993Hck).

## Clinical Significance
HCK (Hematopoietic Cell Kinase) is implicated in various hematological malignancies and solid tumors due to its role in critical signaling pathways. In acute myeloid leukemia (AML), HCK is overexpressed in leukemia stem cells (LSCs), where it regulates self-renewal through CDK6, contributing to drug resistance and relapse (Li2021HCK). In myelodysplastic syndromes (MDS) and AML, HCK is involved in the PI3K/AKT and MAPK/ERK pathways, with its inhibition showing antiproliferative effects on leukemia cells (Roversi2017Hematopoietic). 

In breast cancer, elevated HCK expression is associated with poor prognosis, shorter disease-free survival, and overall survival. It is involved in immune response regulation and is linked to various immune cells and pathways, suggesting its potential as a prognostic biomarker and therapeutic target (Zhu2020HCK). 

In mantle cell lymphoma (MCL), high HCK expression correlates with poor patient survival and is regulated by MYD88 signaling. HCK influences cell proliferation, survival, and adhesion, making it a potential therapeutic target (Lantermans2020Identification). These findings underscore the clinical significance of HCK in cancer biology and its potential as a therapeutic target.

## Interactions
HCK, a member of the Src family of tyrosine kinases, participates in various protein interactions that are crucial for its role in cellular signaling. HCK interacts with the proto-oncogene product Cbl, which acts as a downstream substrate. This interaction is phosphotyrosine-dependent and involves the SH3 and SH2 domains of HCK, facilitating Cbl's phosphorylation and its role as an adaptor molecule in signal transduction (Howlett1999The).

HCK also interacts with the p73 gene product, specifically the p73α isoform, through SH3-polyproline mediated binding. This interaction leads to the phosphorylation of p73α, indicating that p73α is a substrate of HCK's kinase activity (Paliwal2007Regulation). HCK's interaction with p73 is selective, influencing the expression of certain genes and involving the transcriptional co-activator YAP (Paliwal2007Regulation).

In addition, HCK associates with the guanine nucleotide exchange factor C3G through its SH3 domain, leading to the phosphorylation of C3G at Tyr-504. This interaction is significant for inducing apoptosis in various cell lines (Shivakrupa2003Physical).

HCK also binds to actin-associated proteins such as WASP and WIP, and interacts with ELMO1, a component of the CrkII/Dock180/Rac pathway, through SH3-polyproline interactions (Scott2002Identification). These interactions highlight HCK's involvement in integrin-mediated signal transduction and phagocytosis.


## References


[1. (Perlmutter1989Specialized) Roger M. Perlmutter, Jamey D. Marth, Steven F. Ziegler, Alex M. Garvin, Shashi Pawar, Michael P. Cooke, and Kristin M. Abraham. Specialized protein tyrosine kinase proto-oncogenes in hematopoietic cells. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 948(3):245–262, February 1989. URL: http://dx.doi.org/10.1016/0304-419x(89)90001-2, doi:10.1016/0304-419x(89)90001-2. This article has 8 citations.](https://doi.org/10.1016/0304-419x(89)90001-2)

[2. (Scott2002Identification) Margaret Porter Scott, Francesca Zappacosta, Eun Young Kim, Roland S. Annan, and W. Todd Miller. Identification of novel sh3 domain ligands for the src family kinase hck. Journal of Biological Chemistry, 277(31):28238–28246, August 2002. URL: http://dx.doi.org/10.1074/jbc.m202783200, doi:10.1074/jbc.m202783200. This article has 68 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m202783200)

[3. (Guiet2008Hematopoietic) Romain Guiet, Renaud Poincloux, Jerôme Castandet, Louis Marois, Arnaud Labrousse, Véronique Le Cabec, and Isabelle Maridonneau-Parini. Hematopoietic cell kinase (hck) isoforms and phagocyte duties – from signaling and actin reorganization to migration and phagocytosis. European Journal of Cell Biology, 87(8–9):527–542, September 2008. URL: http://dx.doi.org/10.1016/j.ejcb.2008.03.008, doi:10.1016/j.ejcb.2008.03.008. This article has 58 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ejcb.2008.03.008)

[4. (Engen2008Structure) J. R. Engen, T. E. Wales, J. M. Hochrein, M. A. Meyn, S. Banu Ozkan, I. Bahar, and T. E. Smithgall. Structure and dynamic regulation of src-family kinases. Cellular and Molecular Life Sciences, 65(19):3058–3073, June 2008. URL: http://dx.doi.org/10.1007/s00018-008-8122-2, doi:10.1007/s00018-008-8122-2. This article has 145 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-008-8122-2)

[5. (Roversi2017Hematopoietic) Fernanda Marconi Roversi, Fernando Vieira Pericole, João Agostinho Machado-Neto, Adriana da Silva Santos Duarte, Ana Leda Longhini, Flávia Adolfo Corrocher, Bruna Palodetto, Karla Priscila Ferro, Renata Giardini Rosa, Mariana Ozello Baratti, Sergio Verjovski-Almeida, Fabiola Traina, Alessio Molinari, Maurizio Botta, and Sara Teresinha Olalla Saad. Hematopoietic cell kinase (hck) is a potential therapeutic target for dysplastic and leukemic cells due to integration of erythropoietin/pi3k pathway and regulation of erythropoiesis. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(2):450–461, February 2017. URL: http://dx.doi.org/10.1016/j.bbadis.2016.11.013, doi:10.1016/j.bbadis.2016.11.013. This article has 26 citations.](https://doi.org/10.1016/j.bbadis.2016.11.013)

[6. (Li2021HCK) Zheng Li, Fangce Wang, Xiaoxue Tian, Jun Long, Bin Ling, Wenjun Zhang, Jun Xu, and Aibin Liang. Hck maintains the self-renewal of leukaemia stem cells via cdk6 in aml. Journal of Experimental & Clinical Cancer Research, June 2021. URL: http://dx.doi.org/10.1186/s13046-021-02007-4, doi:10.1186/s13046-021-02007-4. This article has 9 citations.](https://doi.org/10.1186/s13046-021-02007-4)

[7. (Paliwal2007Regulation) Preeti Paliwal, Vegesna Radha, and Ghanshyam Swarup. Regulation of p73 by hck through kinase-dependent and independent mechanisms. BMC Molecular Biology, May 2007. URL: http://dx.doi.org/10.1186/1471-2199-8-45, doi:10.1186/1471-2199-8-45. This article has 27 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/1471-2199-8-45)

[8. (Shivakrupa2003Physical) R. Shivakrupa, Vegesna Radha, Ch. Sudhakar, and Ghanshyam Swarup. Physical and functional interaction between hck tyrosine kinase and guanine nucleotide exchange factor c3g results in apoptosis, which is independent of c3g catalytic domain. Journal of Biological Chemistry, 278(52):52188–52194, December 2003. URL: http://dx.doi.org/10.1074/jbc.M310656200, doi:10.1074/jbc.m310656200. This article has 92 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M310656200)

[9. (English1993Hck) B K English, J N Ihle, A Myracle, and T Yi. Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages. The Journal of experimental medicine, 178(3):1017–1022, September 1993. URL: http://dx.doi.org/10.1084/jem.178.3.1017, doi:10.1084/jem.178.3.1017. This article has 94 citations.](https://doi.org/10.1084/jem.178.3.1017)

[10. (Lantermans2020Identification) Hildo C. Lantermans, Marthe Minderman, Annemieke Kuil, Marie-José Kersten, Steven T. Pals, and Marcel Spaargaren. Identification of the src-family tyrosine kinase hck as a therapeutic target in mantle cell lymphoma. Leukemia, 35(3):881–886, June 2020. URL: http://dx.doi.org/10.1038/s41375-020-0934-6, doi:10.1038/s41375-020-0934-6. This article has 15 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41375-020-0934-6)

[11. (Zhu2020HCK) Xudong Zhu, Yixiao Zhang, Yang Bai, Xi Gu, Guanglei Chen, Lisha Sun, Yulun Wang, Xinbo Qiao, Qingtian Ma, Tong Zhu, Jiawen Bu, Jinqi Xue, and Caigang Liu. Hck can serve as novel prognostic biomarker and therapeutic target for breast cancer patients. International Journal of Medical Sciences, 17(17):2773–2789, 2020. URL: http://dx.doi.org/10.7150/ijms.43161, doi:10.7150/ijms.43161. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.7150/ijms.43161)

[12. (Howlett1999The) Christopher J. Howlett, Sabine A. Bisson, Mary E. Resek, Allan W. Tigley, and Stephen M. Robbins. The proto-oncogene p120cblis a downstream substrate of the hck protein-tyrosine kinase. Biochemical and Biophysical Research Communications, 257(1):129–138, April 1999. URL: http://dx.doi.org/10.1006/bbrc.1999.0427, doi:10.1006/bbrc.1999.0427. This article has 26 citations and is from a peer-reviewed journal.](https://doi.org/10.1006/bbrc.1999.0427)