Wednesday 3 December 2003
Protein kinases are one of the largest families of evolutionarily related proteins and comprise one of the most abundant gene families in humans.
About 915 human kinase mutations underlie 67 single-gene diseases, mainly inherited developmental and metabolic disorders and also certain cancers.
receptor tyrosine kinases (Src-family kinases)
cell cycle checkpoint kinases
- Protein kinases are the most common protein domains implicated in cancer, where somatically acquired mutations are known to be functionally linked to a variety of cancers.
- Resequencing studies of protein kinase coding regions have emphasized the importance of sequence and structure determinants of cancer-causing kinase mutations in understanding of the mutation-dependent activation process.
- Integrated bioinformatics resources consolidated and mapped all currently available information on genetic modifications in protein kinase genes with sequence, structure and functional data.
- The integration of diverse data types provided convenient frameworks for kinome-wide study of sequence-based and structure-based signatures of cancer mutations.
- Database-driven analysis revealed a differential enrichment of SNPs categories in functional regions of the kinase domain, demonstrating that a significant number of cancer mutations could fall at structurally equivalent positions (mutational hotspots) within the catalytic core.
- Structurally conserved mutational hotspots can be shared by multiple kinase genes and are often enriched by cancer driver mutations with high oncogenic activity.
- Structural modeling and energetic analysis of the mutational hotspots have suggested a common molecular mechanism of kinase activation by cancer mutations.
- According to a proposed mechanism, structural effect of kinase mutations with a high oncogenic potential may manifest in a significant destabilization of the autoinhibited kinase form, which is likely to drive tumorigenesis at some level.
- Structure-based functional annotation and prediction of cancer mutation effects in protein kinases can facilitate an understanding of the mutation-dependent activation process and inform experimental studies exploring molecular pathology of tumorigenesis. (#19834613#)
phosphorylated protein antibodies
Kinase mutations in human disease: interpreting genotype-phenotype relationships. Lahiry P, Torkamani A, Schork NJ, Hegele RA. Nat Rev Genet. 2010 Jan;11(1):60-74. PMID: #20019687#
Hannah AL. Kinases as drug discovery targets in hematologic malignancies. Curr Mol Med. 2005 Nov;5(7):625-42. PMID: #16305489#
Sequence and structure signatures of cancer mutation hotspots in protein kinases. Dixit A, Yi L, Gowthaman R, Torkamani A, Schork NJ, Verkhivker GM. PLoS One. 2009 Oct 16;4(10):e7485. PMID: #19834613#