MAP4K1

MAP4K1
Identifiers
Aliases	MAP4K1 , HPK1, mitogen-activated protein kinase kinase kinase kinase 1
External IDs	OMIM: 601983; MGI: 1346882; HomoloGene: 5199; GeneCards: MAP4K1; OMA:MAP4K1 - orthologs
Gene location (Human) Chr. Chromosome 19 (human) [1] Band 19q13.2 Start 38,587,641 bp [1] End 38,618,882 bp [1]
Gene location (Mouse) Chr. Chromosome 7 (mouse) [2] Band 7|7 B1 Start 28,681,475 bp [2] End 28,702,704 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte lymph node spleen appendix bone marrow cell blood monocyte tonsil testicle sural nerve Top expressed in mesenteric lymph nodes spleen thymus spermatid blood ankle joint morula granulocyte embryo embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein kinase activity MAP kinase kinase kinase kinase activity protein serine/threonine kinase activity nucleotide binding protein binding ATP binding kinase activity Cellular component cytoplasm membrane intracellular anatomical structure Biological process protein autophosphorylation protein phosphorylation response to stress cell population proliferation intracellular signal transduction peptidyl-serine phosphorylation phosphorylation regulation of mitotic cell cycle regulation of apoptotic process signal transduction stress-activated protein kinase signaling cascade activation of protein kinase activity cellular response to phorbol 13-acetate 12-myristate Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 11184 26411 Ensembl ENSG00000282928 ENSG00000104814 ENSMUSG00000037337 UniProt Q92918 P70218 RefSeq (mRNA) NM_001042600 NM_007181 NM_008279 NM_001355054 RefSeq (protein) NP_001036065 NP_009112 NP_032305 NP_001341983 Location (UCSC) Chr 19: 38.59 – 38.62 Mb Chr 7: 28.68 – 28.7 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Mitogen-activated protein kinase kinase kinase kinase 1 is a protein kinase that in humans is encoded by the MAP4K1 gene. ^[5] It is also known as HPK1 (Hematopoietic Progenitor Kinase 1). The protein has been shown to play a role in JNK activation. ^[6]

Interactions

MAP4K1 has been shown to interact with:

• B-cell linker, ^[7]
• CRK, ^{[8] [9] [10]}
• CRKL, ^{[8] [9] [10]}
• Drebrin-like, ^[11]
• GRAP2, ^[12]
• Grb2, ^{[8] [9] [10] [13]}
• Linker of activated T cells, ^[10] and
• NCK1. ^{[9] [10] [13]}

Optimization of inhibitors of MAP4K1 for upregulating the T cell receptor signaling pathway has produced at least one compound that exhibits antitumor activity in an EMT6 syngeneic mouse model, and is an area of ongoing research. ^[14]

References

1. ENSG00000104814 GRCh38: Ensembl release 89: ENSG00000282928, ENSG00000104814 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000037337 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Hu MC, Qiu WR, Wang X, Meyer CF, Tan TH (Dec 1996). "Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade". Genes Dev. 10 (18): 2251–64. doi: 10.1101/gad.10.18.2251 . PMID   8824585.
6. Chuang HC, Wang X, Tan TH (2016). MAP4K Family Kinases in Immunity and Inflammation. Advances in Immunology. Vol. 129. pp. 277–314. doi:10.1016/bs.ai.2015.09.006. ISBN   9780128047996. PMID   26791862.{{cite book}}: |journal= ignored (help)
7. Tsuji S, Okamoto M, Yamada K, Okamoto N, Goitsuka R, Arnold R, Kiefer F, Kitamura D (Aug 2001). "B cell adaptor containing src homology 2 domain (BASH) links B cell receptor signaling to the activation of hematopoietic progenitor kinase 1". J. Exp. Med. 194 (4): 529–39. doi:10.1084/jem.194.4.529. PMC   2193495 . PMID   11514608.
8. Oehrl W, Kardinal C, Ruf S, Adermann K, Groffen J, Feng GS, Blenis J, Tan TH, Feller SM (Oct 1998). "The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins". Oncogene. 17 (15): 1893–901. doi:10.1038/sj.onc.1202108. PMID   9788432. S2CID   19885101.
9. Ling P, Yao Z, Meyer CF, Wang XS, Oehrl W, Feller SM, Tan TH (Feb 1999). "Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase". Mol. Cell. Biol. 19 (2): 1359–68. doi:10.1128/MCB.19.2.1359. PMC   116064 . PMID   9891069.
10. Ling P, Meyer CF, Redmond LP, Shui JW, Davis B, Rich RR, Hu MC, Wange RL, Tan TH (Jun 2001). "Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling". J. Biol. Chem. 276 (22): 18908–14. doi: 10.1074/jbc.M101485200 . PMID   11279207.
11. Ensenat D, Yao Z, Wang XS, Kori R, Zhou G, Lee SC, Tan TH (Nov 1999). "A novel src homology 3 domain-containing adaptor protein, HIP-55, that interacts with hematopoietic progenitor kinase 1". J. Biol. Chem. 274 (48): 33945–50. doi: 10.1074/jbc.274.48.33945 . PMID   10567356.
12. Ma W, Xia C, Ling P, Qiu M, Luo Y, Tan TH, Liu M (Mar 2001). "Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes". Oncogene. 20 (14): 1703–14. doi:10.1038/sj.onc.1204224. PMID   11313918. S2CID   25646725.
13. Anafi M, Kiefer F, Gish GD, Mbamalu G, Iscove NN, Pawson T (Oct 1997). "SH2/SH3 adaptor proteins can link tyrosine kinases to a Ste20-related protein kinase, HPK1". J. Biol. Chem. 272 (44): 27804–11. doi: 10.1074/jbc.272.44.27804 . PMID   9346925.
14. Shields JD, Baker D, Balazs AY, Bommakanti G, Casella R, Cao S, Cook S, Escobar RA, Fawell S, Gibbons FD, Giblin KA, Goldberg FW, Gosselin E, Grebe T, Hariparsad, N, Hatoum-Mokdad, H, Howells R, Hughes, SJ, Jackson, A, et al. (Feb 2025). "Discovery and Optimization of Pyrazine Carboxamide AX3246, a Selective HPK1 Inhibitor". Journal of Medicinal Chemistry. 68 (4): 4582–4595. doi:10.1021/acs.jmedchem.4c02631. PMID   39928839.