Alternative titles; symbols
HGNC Approved Gene Symbol: MAP3K9
Cytogenetic location: 14q24.2 Genomic coordinates (GRCh38): 14:70,722,526-70,809,513 (from NCBI)
Using the polymerase chain reaction to study mRNA expressed in human epithelial tumor cells, Dorow et al. (1993) identified a member of a new family of protein kinases. The catalytic domain of these kinases had amino acid sequence similarity to both the tyr-specific and the ser/thr-specific kinase classes. Dorow et al. (1993) isolated clones representing 2 members of this new family from a human colonic epithelial cDNA library. The predicted amino acid sequence revealed that, in addition to their unusual nature of the kinase catalytic domains, they contain 2 leu/ile-zipper motifs and a basic sequence near their C-termini. Because they possess domains associated with proteins from 2 distinct functional groups, these kinases were referred to as mixed-lineage kinases (MLK) 1 and 2. MLK1 mRNA was found to be expressed in epithelial tumor cell lines of colonic, breast, and esophageal origin. The similarity score with MLK1 varied from 73 down to 61 for the following tyr PKs; ROS (165020), ABL (189980), EGFR (131550), SRC (190090), TRK (191315), PDGFR (173410, 173490), INSR (147670). The similarity score with MLK1 was 63 for RAF (164760) and 52 for MOS (190060).
By study of rodent/human somatic cell hybrids and isotopic in situ hybridization, Dorow et al. (1993) mapped the MAP3K9 gene to chromosome 14q24.3-q31.
Stark et al. (2012) sequenced 8 melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, Stark et al. (2012) found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 (602448) or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggested that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W33X variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.
While protein kinases vary widely in their primary structures, each contains a catalytic domain of 250 to 300 amino acids, which includes 11 highly conserved motifs or subdomains separated by sequences of amino acids with reduced conservation. The presence of these motifs within a newly characterized sequence is, therefore, strongly predictive of PK activity. Furthermore, specificity of a PK for phosphorylation of either tyr or ser/thr can be predicted by the sequence of 2 of the motifs (VIb and VIII) in which different residues are conserved in each class. PKs with similar substrates or modes of activation cluster into families, whose members share a higher degree of catalytic-domain sequence identity with each other than with other members of the same PK specificity class. Hanks (1991) described 10 families of ser/thr PKs and 11 families of tyr PKs.
Dorow, D. S., Devereux, L., Dietzsch, E., De Kretser, T. Identification of a new family of human epithelial protein kinases containing two leucine/isoleucine-zipper domains. Europ. J. Biochem. 213: 701-710, 1993. [PubMed: 8477742] [Full Text: https://doi.org/10.1111/j.1432-1033.1993.tb17810.x]
Hanks, S. K. Eukaryotic protein kinases. Curr. Opin. Struct. Biol. 1: 369-383, 1991.
Stark, M. S., Woods, S. L., Gartside, M. G., Bonazzi, V. F., Dutton-Regester, K., Aoude, L. G., Chow, D., Sereduk, C., Niemi, N. M., Tang, N., Ellis, J. J., Reid, J., and 18 others. Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. Nature Genet. 44: 165-169, 2012. [PubMed: 22197930] [Full Text: https://doi.org/10.1038/ng.1041]