Mitogen-activated protein kinase kinase kinase 9

Function

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Also plays a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.

Classification

Family (Pfam)

PF07714 PK_Tyr_Ser-Thr, PF14604 SH3_9

InterPro

Kinase-like_dom_sf, MLK1-3_SH3, MLK1-4, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser-Thr/Tyr_kinase_cat_dom, Ser/Thr_kinase_AS, Ser/Thr_Kinases-Pseudokinases, SH3-like_dom_sf, SH3_domain

Functional cluster

Eukaryotic Transcription Factors & related

Experimental structures · PDB · 2

• 3DTC X-ray 2.60A
• 4UY9 X-ray 2.81A

A predicted model is available from AlphaFold.

Gene Ontology · 13

• GO:0005737 cytoplasm
• GO:0005524 ATP binding
• GO:0004706 JUN kinase kinase kinase activity
• GO:0004708 MAP kinase kinase activity
• GO:0140677 molecular function activator activity
• GO:0106310 protein serine kinase activity
• GO:0004674 protein serine/threonine kinase activity
• GO:0006915 apoptotic process
• GO:0006351 DNA-templated transcription
• GO:0043065 positive regulation of apoptotic process
• GO:0046777 protein autophosphorylation
• GO:0006468 protein phosphorylation
• GO:0007165 signal transduction

Drugs targeting this protein · 1

• CEP-1347 inhibitor

Related proteins · sequence + function similarity

• Mitogen-activated protein kinase kinase kinase 9 0.98
• Mitogen-activated protein kinase kinase kinase 10 0.91
• Mitogen-activated protein kinase kinase kinase 10 0.91
• Mitogen-activated protein kinase kinase kinase 21 0.89
• Mitogen-activated protein kinase kinase kinase 10 0.88
• Mitogen-activated protein kinase kinase kinase 10 0.87
• Mitogen-activated protein kinase kinase kinase 12 0.85
• Mitogen-activated protein kinase kinase kinase 11 0.84
• Mitogen-activated protein kinase kinase kinase 11 0.84
• Mitogen-activated protein kinase kinase kinase 11 0.84
• Mitogen-activated protein kinase kinase kinase 12 0.83
• Mitogen-activated protein kinase kinase kinase 12 0.83

Co-cited proteins · studied together in the literature

• Mitogen-activated protein kinase kinase kinase 10 1 shared papers

Literature · 11 cited papers

• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• Large-scale proteomics analysis of the human kinome. Mol. Cell. Proteomics · 2009
• Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. J. Med. Chem. · 2008
• Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues. Int. J. Cancer · 2008
• Patterns of somatic mutation in human cancer genomes. Nature · 2007
• Phosphoregulation of mixed-lineage kinase 1 activity by multiple phosphorylation in the activation loop. Biochemistry · 2004
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Mixed lineage kinase activity of indolocarbazole analogues. Bioorg. Med. Chem. Lett. · 2002
• The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol. Cell. Biol. · 2001
• Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J. Biol. Chem. · 2001
• Identification of a new family of human epithelial protein kinases containing two leucine/isoleucine-zipper domains. Eur. J. Biochem. · 1993