Disease relevance of MAP3K9

• The second part of the study tested the involvement of mixed lineage kinases (MLK) as upstream activators of the JNK pathway in colchicine toxicity, using CEP-1347, a potent MLK inhibitor [1].

High impact information on MAP3K9

• Activation of the Drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of mammalian MLK3 [2].
• We identify AVR(a10) and AVR(k1) of barley powdery mildew fungus, Blumeria graminis f sp hordei (Bgh), and show that they induce both cell death and inaccessibility when transiently expressed in Mla10 and Mlk1 barley (Hordeum vulgare) varieties, respectively [3].
• The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis [4].
• Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation [5].
• MLK-3 and other MLK family kinases are characterized by the presence of multiple protein-protein interaction domains including a tandem leucine/isoleucine zipper (LZs) motif [6].

Biological context of MAP3K9

• The dominant-negative forms of MLK1 and -2 also suppress TGF-beta1-induced cell death [7].
• Phosphoregulation of mixed-lineage kinase 1 activity by multiple phosphorylation in the activation loop [8].
• We initially isolated clones encoding partial cDNAs of MLK1 and 2 from a human colonic cDNA library [9].
• Due to the unique mixture of structural domains within their amino acid sequences, we named the family mixed-lineage kinases (MLK) [9].
• The MLK1 gene has been mapped to human chromosome 14q24.3-31 [10].

Anatomical context of MAP3K9

• As they possess domains associated with proteins from two distinct functional groups, these kinases have been named mixed-lineage kinases (MLK) 1 and 2. mRNA from MLK1 has been found to be expressed in epithelial tumor cell lines of colonic, breast and esophageal origin [10].
• The MLK inhibitor CEP-11004 prevented HeLa cell proliferation by delaying mitotic progression [11].
• Transfection of CHO cells with dominant negative recombinants of MLTKalpha resulted in inhibition of sorbitol-mediated p38 activation, indicating that the mixed-lineage kinase is involved in the activation of p38 by sorbitol [12].
• As expected from a MLK inhibitor, CEP-1347 acted upstream of p38 and c-Jun activation in microglia by dampening the activity of both pathways [13].

Associations of MAP3K9 with chemical compounds

• Immunoblot and mass spectrometry show that MLK1 is threonine (and possibly serine) phosphorylated in or near the activation loop [8].
• Mutation to alanine of any of the four serine or threonine residues in the activation loop reduces both the activity of the recombinant kinase domain and JNK pathway activation driven by full-length MLK1 expressed in mammalian cells [8].

Physical interactions of MAP3K9

• Taken together, these findings strongly suggest that members of the novel MLK family of highly related kinases link small GTP-binding proteins to the JNK signaling pathway [14].

Other interactions of MAP3K9

• PDGF also induced fibronectin and collagen I mRNA expression in control cells, the effects of which were also significantly blocked in MLK 3-transfected cells [15].

References