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Gene Review

MAP4K1  -  mitogen-activated protein kinase kinase...

Homo sapiens

Synonyms: HPK1, Hematopoietic progenitor kinase, MAPK/ERK kinase kinase kinase 1, MEK kinase kinase 1, MEKKK 1, ...
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Disease relevance of MAP4K1


High impact information on MAP4K1

  • These results indicate that HPK1 is a novel functional activator of the JNK/SAPK signaling pathway [3].
  • We have cloned a novel protein kinase, termed hematopoietic progenitor kinase 1 (HPK1), that is expressed predominantly in hematopoietic cells, including early progenitor cells [3].
  • Neither form of HPK1 affected PMA or v-Ras activation of AP-1 and ERK2 [4].
  • Engagement of the TCR or the BCR resulted in a marked induction of HPK1 catalytic activity [4].
  • The serine/threonine kinase HPK1 is a member of the germinal center kinase (GCK) family that has been implicated in the regulation of MAP kinase pathways [4].

Biological context of MAP4K1


Anatomical context of MAP4K1

  • Taken together, our findings demonstrate the functional interaction of HPK1 with Crk and CrkL, reveal the downstream pathways of Crk- and CrkL-induced JNK activation, and highlight a potential role of HPK1 in T-cell activation [9].
  • Thus, activation of major lymphocyte signaling pathways via HPK1 involves (i) relocation, (ii) autophosphorylation, and (iii) transphosphorylation of HPK1 by PKD [8].
  • Here we report that the serine/threonine kinase hematopoietic progenitor kinase 1 (HPK1), which is activated upon antigen-receptor stimulation and which has been implicated in the regulation of MAP kinase pathways, interacts physically and functionally with BLNK in B cells and with SLP-76 in T cells [10].
  • The results demonstrate that exposure of Jurkat cells to DNA-damaging agents is associated with translocation of active c-Abl from nuclei to cytoplasm and binding of c-Abl to HPK1 [11].
  • Using a yeast two-hybrid screen and cotransfection experiments with Cos-1 cells, evidence was adduced that p92 is HPK-1, a serine/threonine-specific protein kinase expressed in hemopoietic cells [12].

Associations of MAP4K1 with chemical compounds


Physical interactions of MAP4K1

  • We found that HPK1 bound to HIP-55 both in vitro and in vivo [15].
  • These findings indicate that activation of HPK1 and formation of HPK1/c-Abl complexes are functionally important in the stress response of hematopoietic cells to genotoxic agents [11].
  • While KHS bound exclusively to Crk family proteins, HPK1 also interacted with both SH3 domains of Grb2 and weakly with Nck, but not with more than 25 other SH3 domains tested [16].
  • A screen for HPK1 binding proteins identified the hematopoietic cell-specific protein 1 (HS1) as a potential HPK1 interaction partner [17].
  • We found that Grap2 interacted with the hematopoietic progenitor kinase 1 (HPK1) in vitro and in Jurkat T cells [18].

Regulatory relationships of MAP4K1


Other interactions of MAP4K1


Analytical, diagnostic and therapeutic context of MAP4K1


  1. Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses. Shui, J.W., Boomer, J.S., Han, J., Xu, J., Dement, G.A., Zhou, G., Tan, T.H. Nat. Immunol. (2007) [Pubmed]
  2. Synthesis of a novel inhibitor against MRSA and VRE: Preparation from zerumbone ring opening material showing histidine-kinase inhibition. Kitayama, T., Iwabuchi, R., Minagawa, S., Sawada, S., Okumura, R., Hoshino, K., Cappiello, J., Utsumi, R. Bioorg. Med. Chem. Lett. (2007) [Pubmed]
  3. Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Hu, M.C., Qiu, W.R., Wang, X., Meyer, C.F., Tan, T.H. Genes Dev. (1996) [Pubmed]
  4. HPK1 is activated by lymphocyte antigen receptors and negatively regulates AP-1. Liou, J., Kiefer, F., Dang, A., Hashimoto, A., Cobb, M.H., Kurosaki, T., Weiss, A. Immunity (2000) [Pubmed]
  5. Hematopoietic progenitor kinase 1 is a component of transforming growth factor beta-induced c-Jun N-terminal kinase signaling cascade. Zhou, G., Lee, S.C., Yao, Z., Tan, T.H. J. Biol. Chem. (1999) [Pubmed]
  6. Caspase-mediated cleavage and functional changes of hematopoietic progenitor kinase 1 (HPK1). Chen, Y.R., Meyer, C.F., Ahmed, B., Yao, Z., Tan, T.H. Oncogene (1999) [Pubmed]
  7. Functional interactions of HPK1 with adaptor proteins. Boomer, J.S., Tan, T.H. J. Cell. Biochem. (2005) [Pubmed]
  8. Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase D1. Arnold, R., Patzak, I.M., Neuhaus, B., Vancauwenbergh, S., Veillette, A., Van Lint, J., Kiefer, F. Mol. Cell. Biol. (2005) [Pubmed]
  9. Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase. Ling, P., Yao, Z., Meyer, C.F., Wang, X.S., Oehrl, W., Feller, S.M., Tan, T.H. Mol. Cell. Biol. (1999) [Pubmed]
  10. Hematopoietic progenitor kinase 1 associates physically and functionally with the adaptor proteins B cell linker protein and SLP-76 in lymphocytes. Sauer, K., Liou, J., Singh, S.B., Yablonski, D., Weiss, A., Perlmutter, R.M. J. Biol. Chem. (2001) [Pubmed]
  11. Interaction of hematopoietic progenitor kinase 1 and c-Abl tyrosine kinase in response to genotoxic stress. Ito, Y., Pandey, P., Sathyanarayana, P., Ling, P., Rana, A., Weichselbaum, R., Tan, T.H., Kufe, D., Kharbanda, S. J. Biol. Chem. (2001) [Pubmed]
  12. Synergistic regulation of immunoreceptor signaling by SLP-76-related adaptor Clnk and serine/threonine protein kinase HPK-1. Yu, J., Riou, C., Davidson, D., Minhas, R., Robson, J.D., Julius, M., Arnold, R., Kiefer, F., Veillette, A. Mol. Cell. Biol. (2001) [Pubmed]
  13. Protein phosphatase 4 is a positive regulator of hematopoietic progenitor kinase 1. Zhou, G., Boomer, J.S., Tan, T.H. J. Biol. Chem. (2004) [Pubmed]
  14. Hematopoietic progenitor kinase 1 (HPK1) negatively regulates prostaglandin E2-induced fos gene transcription. Sawasdikosol, S., Russo, K.M., Burakoff, S.J. Blood (2003) [Pubmed]
  15. A novel src homology 3 domain-containing adaptor protein, HIP-55, that interacts with hematopoietic progenitor kinase 1. Ensenat, D., Yao, Z., Wang, X.S., Kori, R., Zhou, G., Lee, S.C., Tan, T.H. J. Biol. Chem. (1999) [Pubmed]
  16. The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins. Oehrl, W., Kardinal, C., Ruf, S., Adermann, K., Groffen, J., Feng, G.S., Blenis, J., Tan, T.H., Feller, S.M. Oncogene (1998) [Pubmed]
  17. Activation of hematopoietic progenitor kinase-1 by erythropoietin. Nagata, Y., Kiefer, F., Watanabe, T., Todokoro, K. Blood (1999) [Pubmed]
  18. Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes. Ma, W., Xia, C., Ling, P., Qiu, M., Luo, Y., Tan, T.H., Liu, M. Oncogene (2001) [Pubmed]
  19. Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion. Yang, H.S., Matthews, C.P., Clair, T., Wang, Q., Baker, A.R., Li, C.C., Tan, T.H., Colburn, N.H. Mol. Cell. Biol. (2006) [Pubmed]
  20. A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76. Bartolo, V.D., Montagne, B., Salek, M., Jungwirth, B., Carrette, F., Fourtane, J., Sol-Foulon, N., Michel, F., Schwartz, O., Lehmann, W.D., Acuto, O. J. Exp. Med. (2007) [Pubmed]
  21. B cell adaptor containing src homology 2 domain (BASH) links B cell receptor signaling to the activation of hematopoietic progenitor kinase 1. Tsuji, S., Okamoto, M., Yamada, K., Okamoto, N., Goitsuka, R., Arnold, R., Kiefer, F., Kitamura, D. J. Exp. Med. (2001) [Pubmed]
  22. Mona/Gads SH3C binding to hematopoietic progenitor kinase 1 (HPK1) combines an atypical SH3 binding motif, R/KXXK, with a classical PXXP motif embedded in a polyproline type II (PPII) helix. Lewitzky, M., Harkiolaki, M., Domart, M.C., Jones, E.Y., Feller, S.M. J. Biol. Chem. (2004) [Pubmed]
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