title: Mixed lineage kinase MLK4 is activated in colorectal cancers where it synergistically cooperates with activated RAS signaling in driving tumorigenesis.
abstract: Colorectal cancers (CRC) are commonly classified into those with microsatellite instability and those that are microsatellite stable (MSS) but chromosomally unstable. The latter are characterized by poor prognosis and remain largely intractable at the metastatic stage. Comprehensive mutational analyses have revealed that the mixed lineage kinase 4 (MLK4) protein kinase is frequently mutated in MSS CRC with approximately 50% of the mutations occurring in KRAS- or BRAF-mutant tumors. This kinase has not been characterized previously and the relevance of MLK4 somatic mutations in oncogenesis has not been established. We report that MLK4-mutated alleles in CRC are constitutively active and increase the transformation and tumorigenic capacity of RAS-mutated cell lines. Gene expression silencing or targeted knockout of MLK4 impairs the oncogenic properties of KRAS- and BRAF-mutant cancer cells both in vitro and in xenograft models. In establishing the role of MLK4 in intracellular signaling, we show it directly phosphorylates MEK1 (MAP2K1) and that MEK/ERK (MAPK1) signaling is impaired in MLK4 knockout cells. These findings suggest that MLK4 inhibitors may be efficacious in KRAS- and BRAF-mutated CRCs and may provide a new opportunity for targeting such recalcitrant tumors.
authors: Laboratory of Molecular Genetics, IRCC Institute for Cancer Research and Treatment, Candiolo, Torino, Italy.
authors: Miriam
authors: M
authors: Martini
authors: Mariangela
authors: M
authors: Russo
authors: Simona
authors: S
authors: Lamba
authors: Elisa
authors: E
authors: Vitiello
authors: Emily Hannah
authors: EH
authors: Crowley
authors: Francesco
authors: F
authors: Sassi
authors: Davide
authors: D
authors: Romanelli
authors: Milo
authors: M
authors: Frattini
authors: Antonio
authors: A
authors: Marchetti
authors: Alberto
authors: A
authors: Bardelli
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000201:enzymology*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D020930:MAP Kinase Kinase Kinases; C582627:MAP3K21 protein, human; D015689:Oncogene Protein p21(ras)