Alternative titles; symbols
HGNC Approved Gene Symbol: MAP3K21
Cytogenetic location: 1q42.2 Genomic coordinates (GRCh38): 1:233,327,724-233,385,148 (from NCBI)
Mixed-lineage kinases (e.g., MLK1, 600136) belong to the superfamily of MAP kinase kinase kinases (see MAP3K1, 600982). MLK1, MLK2 (MAP3K10; 600137), MLK3 (MAP3K11; 600050), and MLK4 contain both ser/thr and tyr kinases in their catalytic domains and an N-terminal Src homology (SH3) domain, followed by the kinase domain, a leucine zipper region, and a CDC42 (116952)/RAC (602048)-interactive binding (CRIB) motif, but divergent C-terminal regions (summary by Seit-Nebi et al., 2012).
By screening for large cDNAs expressed in brain, Nagase et al. (2001) identified a 490-amino acid protein, which they termed KIAA1804. RT-PCR analysis revealed highest expression in kidney and pancreas.
Using a yeast 2-hybrid screen to identify proteins interacting with the intracellular domain of TLR4 (603030), followed by coprecipitation and immunoprecipitation analyses, Seit-Nebi et al. (2012) determined that both the short MLK4-alpha and long MLK4-beta variants interact with TLR4 through their N-terminal regions, specifically through the kinase domain. Distinctly from MLK3, MLK4-beta does not interact with CDC42. MLK4-beta also does not interact with TRAF6 (602355) or TRAF2 (601895) and does not activate JNK1 (MAPK8; 601158), p38 (MAPK14; 600289), or ERK2 (MAPK1; 176948). Knockdown of MLK4 resulted in increased induction of TNF (191160) expression by lipopolysaccharide, and MLK4 overexpression reduced TNF production. Seit-Nebi et al. (2012) concluded that MLK4 is a negative regulator of TLR4.
By database analysis, Nagase et al. (2001) mapped the KIAA1804 gene (MAP3K21) to chromosome 1.
Nagase, T., Nakayama, M., Nakajima, D., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 8: 85-95, 2001. [PubMed: 11347906] [Full Text: https://doi.org/10.1093/dnares/8.2.85]
Seit-Nebi, A., Cheng, W., Xu, H., Han, J. MLK4 has negative effect on TLR4 signaling. Cell. Molec. Immun. 9: 27-33, 2012. [PubMed: 21602844] [Full Text: https://doi.org/10.1038/cmi.2011.15]