HCK

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.{{Cite journal |last1=Luo |first1=Shuyan |last2=Du |first2=Shaonan |last3=Tao |first3=Mei |last4=Cao |first4=Jingyuan |last5=Cheng |first5=Peng |date=April 2023 |title=Insights on hematopoietic cell kinase: An oncogenic player in human cancer |url=https://linkinghub.elsevier.com/retrieve/pii/S0753332223001270 |journal=Biomedicine & Pharmacotherapy |language=en |volume=160 |pages=114339 |doi=10.1016/j.biopha.2023.114339|pmid=36736283 |doi-access=free }}{{Cite journal |last1=Sicheri |first1=Frank |last2=Moarefi |first2=Ismail |last3=Kuriyan |first3=John |date=February 1997 |title=Crystal structure of the Src family tyrosine kinase Hck |url=https://www.nature.com/articles/385602a0 |journal=Nature |language=en |volume=385 |issue=6617 |pages=602–609 |doi=10.1038/385602a0 |pmid=9024658 |bibcode=1997Natur.385..602S |issn=0028-0836}}{{Cite journal |last1=Young |first1=Matthew A. |last2=Gonfloni |first2=Stefania |last3=Superti-Furga |first3=Giulio |last4=Roux |first4=Benoit |last5=Kuriyan |first5=John |date=April 2001 |title=Dynamic Coupling between the SH2 and SH3 Domains of c-Src and Hck Underlies Their Inactivation by C-Terminal Tyrosine Phosphorylation |url=https://linkinghub.elsevier.com/retrieve/pii/S0092867401003014 |journal=Cell |language=en |volume=105 |issue=1 |pages=115–126 |doi=10.1016/S0092-8674(01)00301-4|pmid=11301007 |doi-access=free }}

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,{{Cite journal |last1=Bosco |first1=Maria C. |last2=Curiel |first2=Rafael E. |last3=Zea |first3=Arnold H. |last4=Malabarba |first4=Maria G. |last5=Ortaldo |first5=John R. |last6=Espinoza-Delgado |first6=Igor |date=2000-05-01 |title=IL-2 Signaling in Human Monocytes Involves the Phosphorylation and Activation of p59 hck 1 |url=https://journals.aai.org/jimmunol/article/164/9/4575/32990/IL-2-Signaling-in-Human-Monocytes-Involves-the |journal=The Journal of Immunology |language=en |volume=164 |issue=9 |pages=4575–4585 |doi=10.4049/jimmunol.164.9.4575 |pmid=10779760 |issn=0022-1767}}{{Cite journal |last1=Smolinska |first1=Maria J. |last2=Page |first2=Theresa H. |last3=Urbaniak |first3=Ania M. |last4=Mutch |first4=Brenda E. |last5=Horwood |first5=Nicole J. |date=2011-12-01 |title=Hck Tyrosine Kinase Regulates TLR4-Induced TNF and IL-6 Production via AP-1 |url=https://journals.aai.org/jimmunol/article/187/11/6043/85550/Hck-Tyrosine-Kinase-Regulates-TLR4-Induced-TNF-and |journal=The Journal of Immunology |language=en |volume=187 |issue=11 |pages=6043–6051 |doi=10.4049/jimmunol.1100967 |pmid=22021612 |issn=0022-1767}} 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.{{Cite journal |last1=Courtney |first1=Adam H. |last2=Amacher |first2=Jeanine F. |last3=Kadlecek |first3=Theresa A. |last4=Mollenauer |first4=Marianne N. |last5=Au-Yeung |first5=Byron B. |last6=Kuriyan |first6=John |last7=Weiss |first7=Arthur |date=August 2017 |title=A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45 |journal=Molecular Cell |language=en |volume=67 |issue=3 |pages=498–511.e6 |doi=10.1016/j.molcel.2017.06.024 |pmc=5558854 |pmid=28735895}} 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.{{Cite journal |last=Klejman |first=A. |date=2002-11-01 |title=The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells |url=http://emboj.embopress.org/cgi/doi/10.1093/emboj/cdf562 |journal=The EMBO Journal |volume=21 |issue=21 |pages=5766–5774 |doi=10.1093/emboj/cdf562 |pmc=131059 |pmid=12411494}}{{Cite journal |last1=Stanglmaier |first1=M |last2=Warmuth |first2=M |last3=Kleinlein |first3=I |last4=Reis |first4=S |last5=Hallek |first5=M |date=2003-02-01 |title=The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains |url=https://www.nature.com/articles/2402778 |journal=Leukemia |language=en |volume=17 |issue=2 |pages=283–289 |doi=10.1038/sj.leu.2402778 |pmid=12592324 |issn=0887-6924}}{{Cite journal |last1=Roversi |first1=Fernanda Marconi |last2=Bueno |first2=Maura Lima Pereira |last3=Pericole |first3=Fernando Viera |last4=Saad |first4=Sara Teresinha Olalla |date=2021-03-25 |title=Hematopoietic Cell Kinase (HCK) Is a Player of the Crosstalk Between Hematopoietic Cells and Bone Marrow Niche Through CXCL12/CXCR4 Axis |journal=Frontiers in Cell and Developmental Biology |volume=9 |doi=10.3389/fcell.2021.634044 |doi-access=free |issn=2296-634X |pmc=8027121 |pmid=33842460}} 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.{{Cite journal |last1=Kanderova |first1=Veronika |last2=Svobodova |first2=Tamara |last3=Borna |first3=Simon |last4=Fejtkova |first4=Martina |last5=Martinu |first5=Vendula |last6=Paderova |first6=Jana |last7=Svaton |first7=Michael |last8=Kralova |first8=Jarmila |last9=Fronkova |first9=Eva |last10=Klocperk |first10=Adam |last11=Pruhova |first11=Stepanka |last12=Lee-Kirsch |first12=Min Ae |last13=Hornofova |first13=Ludmila |last14=Koblizek |first14=Miroslav |last15=Novak |first15=Petr |date=April 2022 |title=Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK |url=https://linkinghub.elsevier.com/retrieve/pii/S0091674921013956 |journal=Journal of Allergy and Clinical Immunology |language=en |volume=149 |issue=4 |pages=1464–1472.e3 |doi=10.1016/j.jaci.2021.07.046|pmid=34536415 }}

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.{{Cite journal |last1=Kong |first1=Xiangxi |last2=Liao |first2=Yajin |last3=Zhou |first3=Lujun |last4=Zhang |first4=Ying |last5=Cheng |first5=Jinbo |last6=Yuan |first6=Zengqiang |last7=Wang |first7=Shukun |date=2020-09-15 |title=Hematopoietic Cell Kinase (HCK) Is Essential for NLRP3 Inflammasome Activation and Lipopolysaccharide-Induced Inflammatory Response In Vivo |journal=Frontiers in Pharmacology |volume=11 |doi=10.3389/fphar.2020.581011 |doi-access=free |issn=1663-9812 |pmc=7523510 |pmid=33041826}} 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. {{Cite journal |last1=Saha |first1=Tanmoy |last2=Mondal |first2=Jayanta |last3=Khiste |first3=Sachin |last4=Lusic |first4=Hrvoje |last5=Hu |first5=Zhang-Wei |last6=Jayabalan |first6=Ruparoshni |last7=Hodgetts |first7=Kevin J. |last8=Jang |first8=Haelin |last9=Sengupta |first9=Shiladitya |last10=Lee |first10=Somin Eunice |last11=Park |first11=Younggeun |last12=Lee |first12=Luke P. |last13=Goldman |first13=Aaron |date=2021-06-24 |title=Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer |journal=Nanophotonics |language=en |volume=10 |issue=12 |pages=3063–3073 |bibcode=2021Nanop..10..142S |doi=10.1515/nanoph-2021-0142 |pmc=8478290 |pmid=34589378 |doi-access=free}}

HCK has been shown to interact with:

{{div col|colwidth=20em}}

• ADAM15{{cite journal | vauthors = Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR | title = Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases | journal = Journal of Biological Chemistry| volume = 277 | issue = 7 | pages = 4999–5007 | date = Feb 2002 | pmid = 11741929 | doi = 10.1074/jbc.M107430200 | doi-access = free}}
• BCR gene,{{cite journal | vauthors = Stanglmaier M, Warmuth M, Kleinlein I, Reis S, Hallek M | title = The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains | journal = Leukemia | volume = 17 | issue = 2 | pages = 283–9 | date = Feb 2003 | pmid = 12592324 | doi = 10.1038/sj.leu.2402778 | s2cid = 8695384 | doi-access = }}{{cite journal | vauthors = Lionberger JM, Wilson MB, Smithgall TE | title = Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck | journal = The Journal of Biological Chemistry | volume = 275 | issue = 24 | pages = 18581–5 | date = Jun 2000 | pmid = 10849448 | doi = 10.1074/jbc.C000126200 | doi-access = free }}
• Cbl gene,{{cite journal | vauthors = Howlett CJ, Robbins SM | title = Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation | journal = Oncogene | volume = 21 | issue = 11 | pages = 1707–16 | date = Mar 2002 | pmid = 11896602 | doi = 10.1038/sj.onc.1205228 | s2cid = 34296309 | doi-access = free }}{{cite journal | vauthors = Howlett CJ, Bisson SA, Resek ME, Tigley AW, Robbins SM | title = The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein-tyrosine kinase | journal = Biochemical and Biophysical Research Communications | volume = 257 | issue = 1 | pages = 129–38 | date = Apr 1999 | pmid = 10092522 | doi = 10.1006/bbrc.1999.0427 }}
• ELMO1,{{cite journal | vauthors = Scott MP, Zappacosta F, Kim EY, Annan RS, Miller WT | title = Identification of novel SH3 domain ligands for the Src family kinase Hck. Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and ELMO1 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 31 | pages = 28238–46 | date = Aug 2002 | pmid = 12029088 | doi = 10.1074/jbc.M202783200 | doi-access = free }}
• Granulocyte colony-stimulating factor receptor,{{cite journal | vauthors = Ward AC, Monkhouse JL, Csar XF, Touw IP, Bello PA | title = The Src-like tyrosine kinase Hck is activated by granulocyte colony-stimulating factor (G-CSF) and docks to the activated G-CSF receptor | journal = Biochemical and Biophysical Research Communications | volume = 251 | issue = 1 | pages = 117–23 | date = Oct 1998 | pmid = 9790917 | doi = 10.1006/bbrc.1998.9441 }}
• RAPGEF1,{{cite journal | vauthors = Shivakrupa R, Radha V, Sudhakar C, Swarup G | title = 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 = The Journal of Biological Chemistry | volume = 278 | issue = 52 | pages = 52188–94 | date = Dec 2003 | pmid = 14551197 | doi = 10.1074/jbc.M310656200 | doi-access = free }}
• RAS p21 protein activator 1,{{cite journal | vauthors = Briggs SD, Bryant SS, Jove R, Sanderson SD, Smithgall TE | title = The Ras GTPase-activating protein (GAP) is an SH3 domain-binding protein and substrate for the Src-related tyrosine kinase, Hck | journal = The Journal of Biological Chemistry | volume = 270 | issue = 24 | pages = 14718–24 | date = Jun 1995 | pmid = 7782336 | doi = 10.1074/jbc.270.24.14718| doi-access = free}} and
• RASA3.

{{Div col end}}

{{reflist}}

{{refbegin | 2}}

• {{cite journal | vauthors = Geyer M, Fackler OT, Peterlin BM | title = Structure--function relationships in HIV-1 Nef. | journal = EMBO Rep. | volume = 2 | issue = 7 | pages = 580–5 | year = 2001 | pmid = 11463741 | pmc = 1083955 | doi = 10.1093/embo-reports/kve141 }}
• {{cite journal | vauthors = Lake JA, Carr J, Feng F, Mundy L, Burrell C, Li P | title = The role of Vif during HIV-1 infection: interaction with novel host cellular factors. | journal = J. Clin. Virol. | volume = 26 | issue = 2 | pages = 143–52 | year = 2003 | pmid = 12600646 | doi = 10.1016/S1386-6532(02)00113-0 }}
• {{cite journal | vauthors = Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M | title = HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication. | journal = J. Biosci. | volume = 28 | issue = 3 | pages = 323–35 | year = 2004 | pmid = 12734410 | doi = 10.1007/BF02970151 | s2cid = 33749514 }}
• {{cite journal | vauthors = Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M | title = HIV/SIV escape from immune surveillance: focus on Nef. | journal = Curr. HIV Res. | volume = 2 | issue = 2 | pages = 141–51 | year = 2004 | pmid = 15078178 | doi = 10.2174/1570162043484924 }}
• {{cite journal | vauthors = Joseph AM, Kumar M, Mitra D | title = Nef: "necessary and enforcing factor" in HIV infection. | journal = Curr. HIV Res. | volume = 3 | issue = 1 | pages = 87–94 | year = 2005 | pmid = 15638726 | doi = 10.2174/1570162052773013 }}
• {{cite journal | vauthors = Stove V, Verhasselt B | title = Modelling thymic HIV-1 Nef effects. | journal = Curr. HIV Res. | volume = 4 | issue = 1 | pages = 57–64 | year = 2006 | pmid = 16454711 | doi = 10.2174/157016206775197583 }}
• {{cite journal | vauthors = Lichtenberg U, Quintrell N, Bishop JM | title = Human protein-tyrosine kinase gene HCK: expression and structural analysis of the promoter region. | journal = Oncogene | volume = 7 | issue = 5 | pages = 849–58 | year = 1992 | pmid = 1373873 }}
• {{cite journal | vauthors = Hradetzky D, Strebhardt K, Rübsamen-Waigmann H | title = 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. | journal = Gene | volume = 113 | issue = 2 | pages = 275–80 | year = 1992 | pmid = 1572549 | doi = 10.1016/0378-1119(92)90407-G }}
• {{cite journal | vauthors = Kim JW, Sim SS, Kim UH, Nishibe S, Wahl MI, Carpenter G, Rhee SG | title = Tyrosine residues in bovine phospholipase C-gamma phosphorylated by the epidermal growth factor receptor in vitro. | journal = J. Biol. Chem. | volume = 265 | issue = 7 | pages = 3940–3 | year = 1990 | doi = 10.1016/S0021-9258(19)39684-X | pmid = 1689310 | doi-access = free }}
• {{cite journal | vauthors = Holtrich U, Bräuninger A, Strebhardt K, Rübsamen-Waigmann H | title = Two additional protein-tyrosine kinases expressed in human lung: fourth member of the fibroblast growth factor receptor family and an intracellular protein-tyrosine kinase. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 88 | issue = 23 | pages = 10411–5 | year = 1992 | pmid = 1720539 | pmc = 52938 | doi = 10.1073/pnas.88.23.10411 | doi-access = free }}
• {{cite journal | vauthors = Lock P, Ralph S, Stanley E, Boulet I, Ramsay R, Dunn AR | title = Two isoforms of murine hck, generated by utilization of alternative translational initiation codons, exhibit different patterns of subcellular localization. | journal = Mol. Cell. Biol. | volume = 11 | issue = 9 | pages = 4363–70 | year = 1991 | pmid = 1875927 | pmc = 361298 | doi = 10.1128/mcb.11.9.4363}}
• {{cite journal | vauthors = Ziegler SF, Marth JD, Lewis DB, Perlmutter RM | title = Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin. | journal = Mol. Cell. Biol. | volume = 7 | issue = 6 | pages = 2276–85 | year = 1987 | pmid = 3453117 | pmc = 365352 | doi = 10.1128/mcb.7.6.2276}}
• {{cite journal | vauthors = Lee CH, Leung B, Lemmon MA, Zheng J, Cowburn D, Kuriyan J, Saksela K | title = A single amino acid in the SH3 domain of Hck determines its high affinity and specificity in binding to HIV-1 Nef protein. | journal = EMBO J. | volume = 14 | issue = 20 | pages = 5006–15 | year = 1995 | pmid = 7588629 | pmc = 394604 | doi = 10.1002/j.1460-2075.1995.tb00183.x}}
• {{cite journal | vauthors = Liao F, Shin HS, Rhee SG | title = In vitro tyrosine phosphorylation of PLC-gamma 1 and PLC-gamma 2 by src-family protein tyrosine kinases. | journal = Biochem. Biophys. Res. Commun. | volume = 191 | issue = 3 | pages = 1028–33 | year = 1993 | pmid = 7682059 | doi = 10.1006/bbrc.1993.1320 | url = https://zenodo.org/record/1229412 | type = Submitted manuscript }}
• {{cite journal | vauthors = Briggs SD, Bryant SS, Jove R, Sanderson SD, Smithgall TE | title = The Ras GTPase-activating protein (GAP) is an SH3 domain-binding protein and substrate for the Src-related tyrosine kinase, Hck. | journal = J. Biol. Chem. | volume = 270 | issue = 24 | pages = 14718–24 | year = 1995 | pmid = 7782336 | doi = 10.1074/jbc.270.24.14718 | doi-access = free}}
• {{cite journal | vauthors = Robbins SM, Quintrell NA, Bishop JM | title = Myristoylation and differential palmitoylation of the HCK protein-tyrosine kinases govern their attachment to membranes and association with caveolae. | journal = Mol. Cell. Biol. | volume = 15 | issue = 7 | pages = 3507–15 | year = 1995 | pmid = 7791757 | pmc = 230587 | doi = 10.1128/mcb.15.7.3507}}
• {{cite journal | vauthors = Saksela K, Cheng G, Baltimore D | title = 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. | journal = EMBO J. | volume = 14 | issue = 3 | pages = 484–91 | year = 1995 | pmid = 7859737 | pmc = 398106 | doi = 10.1002/j.1460-2075.1995.tb07024.x}}
• {{cite journal | vauthors = Cheng G, Ye ZS, Baltimore D | title = Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 91 | issue = 17 | pages = 8152–5 | year = 1994 | pmid = 8058772 | pmc = 44563 | doi = 10.1073/pnas.91.17.8152 | bibcode = 1994PNAS...91.8152C | doi-access = free }}
• {{cite journal | vauthors = Wang AV, Scholl PR, Geha RS | title = Physical and functional association of the high affinity immunoglobulin G receptor (Fc gamma RI) with the kinases Hck and Lyn. | journal = J. Exp. Med. | volume = 180 | issue = 3 | pages = 1165–70 | year = 1994 | pmid = 8064233 | pmc = 2191633 | doi = 10.1084/jem.180.3.1165 }}

{{refend}}

{{PDB Gallery|geneid=3055}}

{{Tyrosine kinases}}

{{Enzymes}}

{{Portal bar|Biology|border=no}}

Category:Tyrosine kinases