Disease relevance of LYK5

• We review evidence that the pseudokinase STRAD controls the function of the tumour suppressor kinase LKB1 and that a single amino acid substitution within the pseudokinase domain of the tyrosine kinase JAK2 leads to several malignant myeloproliferative disorders [1].
• RESULTS: Loss of the marker near the STRAD locus was seen in 13 of 29 informative cases, including all gastric adenocarcinomas [2].
• STRAD in Peutz-Jeghers syndrome and sporadic cancers [2].
• The STRAD gene, encoding an LKB1 interacting protein that activates LKB1, which subsequently leads to polarisation of cells, is an interesting candidate for a second PJS gene and a potential tumour suppressor gene in sporadic carcinomas [2].

High impact information on LYK5

• We have now constructed intestinal epithelial cell lines in which inducible STRAD activates LKB1 [3].
• Interestingly, 12 of these mutants failed to interact with STRAD-MO25 [4].
• Specific LOH of the STRAD marker was found in four of 29 informative cases [2].
• CONCLUSIONS: Despite the frequent occurrence of LOH in the STRAD region, these results indicate that inactivation of the STRAD gene is not essential in the sporadic adenocarcinomas studied, although it is possible that STRAD may be inactivated in different ways [2].
• For these patients all exons and exon-intron boundaries of the STRAD gene were sequenced, but no somatic mutations were identified [2].

Biological context of LYK5

• Furthermore, no germline STRAD mutations were found in 10 patients with PJS and family members without LKB1 germline mutation [2].
• A complex with the STRAD alpha peptide reveals a hydrophobic pocket that is involved in a unique and specific interaction with the Trp-Glu-Phe motif, further supported by mutagenesis studies [5].

Physical interactions of LYK5

• MO25 alpha binds directly to a conserved Trp-Glu-Phe sequence at the STRAD alpha C terminus, markedly enhancing binding of STRAD alpha to LKB1 and increasing LKB1 catalytic activity [5].

Regulatory relationships of LYK5

• Our results imply that STRAD plays a key role in regulating the tumour suppressor activities of LKB1 [6].

Other interactions of LYK5

• Analysis of the LKB1-STRAD-MO25 complex [4].

References