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Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.

Velho S, Oliveira C, Paredes J, Sousa S, Leite M, Matos P, Milanezi F, Ribeiro AS, Mendes N, Licastro D, Karhu A, Oliveira MJ, Ligtenberg M, Hamelin R, Carneiro F, Lindblom A, Peltomaki P, Castedo S, Schwartz S, Jordan P, Aaltonen LA, Hofstra RM, Suriano G, Stupka E, Fialho AM, Seruca R - Hum. Mol. Genet. (2009)

Bottom Line: Mixed lineage kinase 3 (MLK3) is a serine/threonine kinase, regulating MAPkinase signalling, in which cancer-associated mutations have never been reported.MLK3 mutations were significantly associated with MSI phenotype in primary tumours (P = 0.0005), occurring in 21% of the MSI carcinomas.Further, we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant.

View Article: PubMed Central - PubMed

Affiliation: IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.

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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Related in: MedlinePlus

Summary of the localization of missense mutations in MLK3 gene found in MSI primary gastrointestinal carcinomas and cell lines. The upper diagram depicts the protein sequence domain architecture, indicating the affected residue and its amino acid change (top), nucleotide start-end coordinates (top) and amino acid start-end coordinates (bottom) for each domain. Below, the wild-type amino acid residue is shown for 20 eukaryotic species, and the conservation for each affected residue is summarized in the bottom two rows, one indicating the conservation in mammalian orthologues (n = 4) and the next in all eukaryotic homologues (n = 16).
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DDP536F1: Summary of the localization of missense mutations in MLK3 gene found in MSI primary gastrointestinal carcinomas and cell lines. The upper diagram depicts the protein sequence domain architecture, indicating the affected residue and its amino acid change (top), nucleotide start-end coordinates (top) and amino acid start-end coordinates (bottom) for each domain. Below, the wild-type amino acid residue is shown for 20 eukaryotic species, and the conservation for each affected residue is summarized in the bottom two rows, one indicating the conservation in mammalian orthologues (n = 4) and the next in all eukaryotic homologues (n = 16).

Mentions: From the 24 MLK3 mutated MSI cases, 15 (62.5%) displayed somatic missense mutations (Table 1), which are depicted in Figure 1. Seventy percent of these missense mutations occurred in previously described functional domains (Fig. 1) (6,13); and more than 80% affected MLK3 residues which have been evolutionarily conserved as far in evolution as Drosophila melanogaster (Fig. 1).


Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.

Velho S, Oliveira C, Paredes J, Sousa S, Leite M, Matos P, Milanezi F, Ribeiro AS, Mendes N, Licastro D, Karhu A, Oliveira MJ, Ligtenberg M, Hamelin R, Carneiro F, Lindblom A, Peltomaki P, Castedo S, Schwartz S, Jordan P, Aaltonen LA, Hofstra RM, Suriano G, Stupka E, Fialho AM, Seruca R - Hum. Mol. Genet. (2009)

Summary of the localization of missense mutations in MLK3 gene found in MSI primary gastrointestinal carcinomas and cell lines. The upper diagram depicts the protein sequence domain architecture, indicating the affected residue and its amino acid change (top), nucleotide start-end coordinates (top) and amino acid start-end coordinates (bottom) for each domain. Below, the wild-type amino acid residue is shown for 20 eukaryotic species, and the conservation for each affected residue is summarized in the bottom two rows, one indicating the conservation in mammalian orthologues (n = 4) and the next in all eukaryotic homologues (n = 16).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2807374&req=5

DDP536F1: Summary of the localization of missense mutations in MLK3 gene found in MSI primary gastrointestinal carcinomas and cell lines. The upper diagram depicts the protein sequence domain architecture, indicating the affected residue and its amino acid change (top), nucleotide start-end coordinates (top) and amino acid start-end coordinates (bottom) for each domain. Below, the wild-type amino acid residue is shown for 20 eukaryotic species, and the conservation for each affected residue is summarized in the bottom two rows, one indicating the conservation in mammalian orthologues (n = 4) and the next in all eukaryotic homologues (n = 16).
Mentions: From the 24 MLK3 mutated MSI cases, 15 (62.5%) displayed somatic missense mutations (Table 1), which are depicted in Figure 1. Seventy percent of these missense mutations occurred in previously described functional domains (Fig. 1) (6,13); and more than 80% affected MLK3 residues which have been evolutionarily conserved as far in evolution as Drosophila melanogaster (Fig. 1).

Bottom Line: Mixed lineage kinase 3 (MLK3) is a serine/threonine kinase, regulating MAPkinase signalling, in which cancer-associated mutations have never been reported.MLK3 mutations were significantly associated with MSI phenotype in primary tumours (P = 0.0005), occurring in 21% of the MSI carcinomas.Further, we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant.

View Article: PubMed Central - PubMed

Affiliation: IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.

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.

Show MeSH
Related in: MedlinePlus