ArticleHuman molecular genetics2010
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.
Article in Human molecular genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 28 citations in OpenAlex.
- LATS1 Regulates Mixed-Lineage Kinase 3 (MLK3) Subcellular Localization and MLK3-Mediated Invasion in Ovarian Epithelial Cells.Molecular and cellular biology · 2021Article
- The regulatory function of mixed lineage kinase 3 in tumor and host immunity.Pharmacology & therapeutics · 2021Review
- miR-7 Suppresses Tumor Progression by Directly Targeting MAP3K9 in Pancreatic Cancer.Molecular therapy. Nucleic acids · 2018Article
- MLK3 phosphorylation by ERK1/2 is required for oxidative stress-induced invasion of colorectal cancer cells.Oncogene · 2018Article
- MLK3 Signaling in Cancer Invasion.Cancers · 2016Review
- Causes and consequences of microsatellite instability in gastric carcinogenesis.World journal of gastroenterology · 2014Review
- Mixed-lineage kinase 3 deficiency promotes neointima formation through increased activation of the RhoA pathway in vascular smooth muscle cells.Arteriosclerosis, thrombosis, and vascular biology · 2014Article
- Domain specificity of MAP3K family members, MLK and Tak1, for JNK signaling in Drosophila.Genetics · 2014Article
- Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors.Nature communications · 2014Article
- Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation.BMC cancer · 2014Article
- SDM--a server for predicting effects of mutations on protein stability and malfunction.Nucleic acids research · 2011Article
- Meet me halfway: when genomics meets structural bioinformatics.Journal of cardiovascular translational research · 2011Article
- Regulation of mixed lineage kinase 3 is required for Neurofibromatosis-2-mediated growth suppression in human cancer.Oncogene · 2011Article
- Mixed lineage kinase-3/JNK1 axis promotes migration of human gastric cancer cells following gastrin stimulation.Molecular endocrinology (Baltimore, Md.) · 2010Article
Corrections and comments
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Authors and funding
26 authors at 10 institutions in 7 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mixed lineage kinase 3 (MLK3) is a serine/threonine kinase, regulating MAPkinase signalling, in which cancer-associated mutations have never been reported. In this study, 174 primary gastrointestinal cancers (48 hereditary and 126 sporadic forms) and 7 colorectal cancer cell lines were screened for MLK3 mutations. MLK3 mutations were significantly associated with MSI phenotype in primary tumours (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 points to the functional relevance of MLK3 missense mutations, which cluster in the kinase domain. Further, the model shows that most of the altered residues in the kinase domain probably affect MLK3 scaffold properties, instead of its kinase activity. MLK3 missense mutations showed transforming capacity in vitro and cells expressing the mutant gene were able to develop locally invasive tumours, when subcutaneously injected in nude mice. Interestingly, in primary tumours, MLK3 mutations occurred in KRAS and/or BRAF wild-type carcinomas, although not being mutually exclusive genetic events. In conclusion, we have demonstrated for the first time the presence of MLK3 mutations in cancer and its association to mismatch repair deficiency. Further, we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.