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protein kinases

Wednesday 3 December 2003


Definition: Protein kinases are one of the largest families of evolutionarily related proteins and comprise one of the most abundant gene families in humans.

Protein kinases are a large family of approximately 530 highly conserved enzymes that transfer a γ-phosphate group from ATP to a variety of amino acid residues, such as tyrosine, serine, and threonine, that serves as a ubiquitous mechanism for cellular signal transduction.

The clinical success of a number of kinase-directed drugs and the frequent observation of disease causing mutations in protein kinases suggest that a large number of kinases may represent therapeutically relevant targets.

To date, the majority of clinical and preclinical kinase inhibitors are ATP competitive, non-covalent inhibitors that achieve selectivity through recognition of unique features of particular protein kinases.

Recently, there has been renewed interest in the development of irreversible inhibitors that form covalent bonds with cysteine or other nucleophilic residues in the ATP-binding pocket.

Irreversible kinase inhibitors have a number of potential advantages including prolonged pharmacodynamics, suitability for rational design, high potency, and ability to validate pharmacological specificity through mutation of the reactive cysteine residue.


- receptor tyrosine kinases (Src-family kinases)
- serine/threonine kinases
- cell cycle checkpoint kinases
- cyclin-dependent kinases
- Abl-family kinases
- mitogen-activated kinases
- p21-activated kinases
- Ca(2+)/calmodulin-dependent kinases


About 915 human kinase mutations underlie 67 single-gene diseases, mainly inherited developmental and metabolic disorders and also certain cancers.

- Cancer

  • 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)



See also

- kinome
- kinomics
- protein phosphorylation
- phosphorylated protein antibodies

Open References

- Developing irreversible inhibitors of the protein kinase cysteinome. Liu Q, Sabnis Y, Zhao Z, Zhang T, Buhrlage SJ, Jones LH, Gray NS. Chem Biol. 2013 Feb 21;20(2):146-59. doi : 10.1016/j.chembiol.2012.12.006 PMID: 23438744 [Free]


- 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