Alternative titles; symbols
HGNC Approved Gene Symbol: MAP3K11
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:65,597,757-65,614,221 (from NCBI)
Using RT-PCR and cDNA library screening, Ing et al. (1994) identified MAP3K11, a novel protein kinase, from human thymus. The deduced open reading frame, derived from sequencing a 3.5-kb MAP3K11 cDNA, encodes a protein of 847 amino acids. Structural features include an SH3 domain in the absence of an SH2 domain, a region containing 2 leucine zippers with an adjacent C-terminal basic region, and a proline rich region. The kinase showed homology with the mixed-lineage family of protein kinases (MLKs) and shared the unusual leucine zipper-basic motif found in previously identified MLK kinases; Ing et al. (1994) therefore called the protein MLK3. By Northern blot analysis, MAP3K11 mRNA was detected in a wide variety of normal and transformed human cell lines and tissues.
Using small interfering RNA (siRNA), Chadee and Kyriakis (2004) found that MLK3 was required for both mitogen and cytokine activation of JNK (see MAPK8; 601158), ERK (see MAPK3; 601795), and p38 (MAPK14; 600289) in several human cell lines. Silencing MLK3 substantially blocked serum-stimulated phosphorylation of RB1 (614041) in intestinal and lung fibroblast cell lines, and it prevented serum-simulated proliferation of tumor cells bearing oncogenic KRAS2 (190070) or loss-of-function NF1 (613113) or NF2 (607379) mutations. Proliferation of tumor cells bearing activating RAF1 (164760) or BRAF (164757) mutations was unaffected by MLK3 silencing. Chadee and Kyriakis (2004) also observed some cell type-specific effects of MLK3 silencing, and murine Mlk3 siRNA, which differs from the 21-bp human siRNA at 2 positions, did not silence MLK3 in human cells.
Consistent with the observation that MLK3 is required for BRAF phosphorylation, Chadee et al. (2006) found that silencing MLK3 in human embryonic kidney cells completely abrogated mitogen activation of BRAF, but MLK3 kinase activity was not required for BRAF activation. Coimmunoprecipitation experiments identified MLK3 as a component of the BRAF/RAF1 complex, and MLK3 was required for integrity of the complex and for activation of ERK by the complex. Mlk3 interacted with Nf2 in rodent cells, and Nf2 disrupted protein-protein interactions within the Braf/Raf1/Mlk3 complex. Chadee et al. (2006) concluded that MLK3 is a signal-integrating kinase with conventional MAP3K catalytic activity and additional noncatalytic functions that contribute to RAF/ERK signaling.
Using fluorescence in situ hybridization, Ing et al. (1994) mapped the MAP3K11 gene to chromosome 11q13.1-q13.3. Courseaux et al. (1996) used a combination of methods to refine maps of the approximately 5-Mb region of 11q13 that includes MEN1 (131100). They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MAP3K11, RELA]--FOSL1--SEA--CFL1--tel.
Velho et al. (2010) screened 174 primary gastrointestinal cancers (48 hereditary and 126 sporadic forms) and 7 colorectal cancer cell lines for MLK3 mutations. MLK3 mutations were significantly associated with microsatellite instability (MSI) phenotype in primary tumors (p = 0.0005), occurring in 21% of the MSI carcinomas. Most MLK3 somatic mutations identified were of the missense type (62.5%), and more than 80% of them affected evolutionarily conserved residues. A predictive 3D model demonstrated that MLK3 missense mutations clustered in the kinase domain but probably affected scaffold properties rather than kinase activity. MLK3 missense mutations showed transforming capacity in vitro, and cells expressing the mutant gene were able to develop locally invasive tumors when subcutaneously injected in nude mice. In primary tumors, MLK3 mutations occurred in KRAS and/or BRAF wildtype carcinomas, although not being mutually exclusive genetic events.
Chadee, D. N., Kyriakis, J. M. MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. Nature Cell Biol. 6: 770-776, 2004. [PubMed: 15258589] [Full Text: https://doi.org/10.1038/ncb1152]
Chadee, D. N., Xu, D., Hung, G., Andalibi, A., Lim, D. J., Luo, Z., Gutmann, D. H., Kyriakis, J. M. Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein. Proc. Nat. Acad. Sci. 103: 4463-4468, 2006. [PubMed: 16537381] [Full Text: https://doi.org/10.1073/pnas.0510651103]
Courseaux, A., Grosgeorge, J., Gaudray, P., Pannett, A. A. J., Forbes, S. A., Williamson, C., Bassett, D., Thakker, R. V., Teh, B. T., Farnebo, F., Shepherd, J., Skogseid, B., Larsson, C., Giraud, S., Zhang, C. X., Salandre, J., Calender, A. Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. Genomics 37: 354-365, 1996. [PubMed: 8938448]
Ing, Y. L., Leung, I. W. L., Heng, H. H. Q., Tsui, L.-C., Lassam, N. J. MLK-3: identification of a widely-expressed protein kinase bearing an SH3 domain and a leucine zipper-basic region domain. Oncogene 9: 1745-1750, 1994. [PubMed: 8183572]
Velho, S., Oliveira, C., Paredes, J., Sousa, S., Leite, M., Matos, P., Milanezi, F., Ribeiro, A. S., Mendes, N., Licastro, D., Karhu, A., Oliveira, M. J., and 14 others. Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. Hum. Molec. Genet. 19: 697-706, 2010. [PubMed: 19955118] [Full Text: https://doi.org/10.1093/hmg/ddp536]