mitogen-activated protein kinase kinase kinase kinase 1 | KHS subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

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mitogen-activated protein kinase kinase kinase kinase 1

  Target has curated data in GtoImmuPdb

Target id: 2085

Nomenclature: mitogen-activated protein kinase kinase kinase kinase 1

Abbreviated Name: HPK1

Family: KHS subfamily

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 821 19q13.1-q13.4 MAP4K1 mitogen-activated protein kinase kinase kinase kinase 1
Mouse - 827 7 B1 Map4k1 mitogen-activated protein kinase kinase kinase kinase 1
Rat - 827 1 q21 Map4k1 mitogen activated protein kinase kinase kinase kinase 1
Previous and Unofficial Names
hematopoietic progenitor kinase 1 | MAPK/ERK kinase kinase kinase 1
Database Links
BRENDA 2.7.11.1
ChEMBL Target CHEMBL5749 (Hs)
Ensembl Gene ENSG00000104814 (Hs), ENSMUSG00000037337 (Mm), ENSRNOG00000020505 (Rn)
Entrez Gene 11184 (Hs), 26411 (Mm), 292763 (Rn)
Human Protein Atlas ENSG00000104814 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:11184 (Hs), mmu:26411 (Mm), rno:292763 (Rn)
OMIM 601983 (Hs)
RefSeq Nucleotide NM_001042600 (Hs), NM_008279 (Mm), NM_001106243 (Rn)
RefSeq Protein NP_001036065 (Hs), NP_032305 (Mm), NP_001099713 (Rn)
UniProtKB Q92918 (Hs), P70218 (Mm)
Wikipedia MAP4K1 (Hs)
Enzyme Reaction
EC Number: 2.7.11.1
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 3,10
Key to terms and symbols Click column headers to sort
Target used in screen: HPK1
Ligand Sp. Type Action Affinity Parameter
staurosporine Hs Inhibitor Inhibition 8.4 pKd
bosutinib Hs Inhibitor Inhibition 7.8 pKd
SU-14813 Hs Inhibitor Inhibition 7.8 pKd
sunitinib Hs Inhibitor Inhibition 7.8 pKd
lestaurtinib Hs Inhibitor Inhibition 7.4 pKd
crizotinib Hs Inhibitor Inhibition 7.4 pKd
dovitinib Hs Inhibitor Inhibition 7.4 pKd
foretinib Hs Inhibitor Inhibition 7.4 pKd
KW-2449 Hs Inhibitor Inhibition 7.2 pKd
tozasertib Hs Inhibitor Inhibition 7.1 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
HPK1 inhibits T-cell receptor (TCR) signaling via a mechanism that induces phosphorylation and ubiquitination of SLP-76, it inhibits B-cell receptor signaling by inducing phosphorylation and ubiquitination of BLNK [9].
Cell Type Associations
Immuno Cell Type:  Mast cells
Cell Ontology Term:   mast cell (CL:0000097)
References:  2
Immuno Cell Type:  T cells
References:  2,4-5
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
References:  2
Immuno Cell Type:  Macrophages & monocytes
Cell Ontology Term:   macrophage (CL:0000235)
References:  2
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   neutrophil (CL:0000775)
References:  2
Immuno Cell Type:  Dendritic cells
Cell Ontology Term:   dendritic cell (CL:0000451)
References:  2
Physiological Consequences of Altering Gene Expression
Mice with hpk1 knock-out show enhanced T cell activation, increased cytokine production, and increased antibody production after KLH immunization. These findings confirm that hpk1 is a negative regulator of T cell receptor signalling and T cell-mediated immune responses.
Species:  Mouse
Tissue: 
Technique: 
References:  7
Hpk1 null mice are more susceptible to experimental autoimmune encephalomyelitis indiction.
Species:  Mouse
Tissue: 
Technique: 
References:  7
Dendritic cells from hpk1-deficient mice produce higher levels of co-stimulatory molecules and proinflammatory cytokines than their wild type counterpatrs.
Species:  Mouse
Tissue: 
Technique: 
References:  1
General Comments
Hematopoietic progenitor kinase 1 (HPK1) regulates stress responses, proliferation, and apoptosis in hematopoietic cells. HPK1 has been identified as a novel target for cancer immunotherapy, whose inhibition may activate anti-tumour activity of both dendritic cells and T cells [6]. In contrast, a specific role of HPK1 as a novel tumor suppressor has been suggested by studies in pancreatic cancer [8].

References

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1. Alzabin S, Bhardwaj N, Kiefer F, Sawasdikosol S, Burakoff S. (2009) Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation. J. Immunol., 182 (10): 6187-94. [PMID:19414772]

2. Chuang HC, Wang X, Tan TH. (2016) MAP4K Family Kinases in Immunity and Inflammation. Adv. Immunol., 129: 277-314. [PMID:26791862]

3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

4. Hu MC, Qiu WR, Wang X, Meyer CF, Tan TH. (1996) Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes Dev., 10 (18): 2251-64. [PMID:8824585]

5. Kiefer F, Tibbles LA, Anafi M, Janssen A, Zanke BW, Lassam N, Pawson T, Woodgett JR, Iscove NN. (1996) HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. EMBO J., 15 (24): 7013-25. [PMID:9003777]

6. Sawasdikosol S, Zha R, Yang B, Burakoff S. (2012) HPK1 as a novel target for cancer immunotherapy. Immunol. Res., 54 (1-3): 262-5. [PMID:22477524]

7. Shui JW, Boomer JS, Han J, Xu J, Dement GA, Zhou G, Tan TH. (2007) Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses. Nat. Immunol., 8 (1): 84-91. [PMID:17115060]

8. Wang H, Song X, Logsdon C, Zhou G, Evans DB, Abbruzzese JL, Hamilton SR, Tan TH, Wang H. (2009) Proteasome-mediated degradation and functions of hematopoietic progenitor kinase 1 in pancreatic cancer. Cancer Res., 69 (3): 1063-70. [PMID:19141650]

9. Wang X, Li JP, Kuo HK, Chiu LL, Dement GA, Lan JL, Chen DY, Yang CY, Hu H, Tan TH. (2012) Down-regulation of B cell receptor signaling by hematopoietic progenitor kinase 1 (HPK1)-mediated phosphorylation and ubiquitination of activated B cell linker protein (BLNK). J. Biol. Chem., 287 (14): 11037-48. [PMID:22334673]

10. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

How to cite this page

KHS subfamily: mitogen-activated protein kinase kinase kinase kinase 1. Last modified on 05/06/2018. Accessed on 20/05/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2085.