Mitogen-activated protein kinase kinase kinase kinase 1

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Function

Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) or hematopoietic progenitor kinase (HPK1) modulates cell cycle through MAPK and DNA damage/repair pathways. HPK1 is a member of the serine/threonine kinases and is a prominent regulator in adaptive immunity by downregulating T-cell receptor signaling and B-cell receptor signaling via phosphorylation and ubiquitination[1].

Relevance

HPK1 is over expressed in acute myeloid leukemia cell lines and hence is a potential target for development of therapies to it[2]. Mice that received HPK1 became resistant to lung tumor growth[3].

Structural highlights

The 3D structure of the non-phosphorylated HPK1 kinase domain dimer shows the interactions of the which contain the . The activation loop contains the (colored in lightsalmon) which regulates the catalysis of the kinase and is involved in the binding of ATP. The cancer drug [4].

HPK1 3D structures

3D structures of HPK1


Human HPK1 kinase domain dimer (cyan, green) complex with cancer drug sunitinib (PDB code 6nfy)

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ He TS, Huang J, Chen T, Zhang Z, Cai K, Yu J, Xu LG. The Kinase MAP4K1 Inhibits Cytosolic RNA-Induced Antiviral Signaling by Promoting Proteasomal Degradation of TBK1/IKKε. Microbiol Spectr. 2021 Dec 22;9(3):e0145821. PMID:34908452 doi:10.1128/Spectrum.01458-21
  2. ↑ Ling Q, Li F, Zhang X, Mao S, Lin X, Pan J, Ye W, Wei W, Qian Y, Hu C, Huang X, Wang J, Wang H, Huang J, Wang Y, Jin J. MAP4K1 functions as a tumor promotor and drug mediator for AML via modulation of DNA damage/repair system and MAPK pathway. EBioMedicine. 2021 Jul;69:103441. PMID:34166980 doi:10.1016/j.ebiom.2021.103441
  3. ↑ Sawasdikosol S, Zha R, Yang B, Burakoff S. HPK1 as a novel target for cancer immunotherapy. Immunol Res. 2012 Dec;54(1-3):262-5. PMID:22477524 doi:10.1007/s12026-012-8319-1
  4. ↑ Johnson E, McTigue M, Gallego RA, Johnson TW, Timofeevski S, Maestre M, Fisher TS, Kania R, Sawasdikosol S, Burakoff S, Cronin CN. Multiple conformational states of the HPK1 kinase domain in complex with sunitinib reveal the structural changes accompanying HPK1 trans-regulation. J Biol Chem. 2019 Apr 24. pii: AC119.007466. doi: 10.1074/jbc.AC119.007466. PMID:31018963 doi:http://dx.doi.org/10.1074/jbc.AC119.007466

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