Standard Kinase Classification Scheme

The standard protein kinase classification scheme [1, 2] classifies protein kinases into groups, families, and subfamilies, on the basis of their functions, their sequence and structural similarity, and their evolutionary history. The system is highly curated and designed to be of maximal practical value, rather than created by absolute rules. Groups generally relate to broad substrate site specificity (e.g. TKs phosphorylate on tyrosine, and CMGC usually phosphorylate residues next to proline), Families group related kinases by both sequence similarity and broad biological function, and some but not all families are subdivided into Subfamilies that have finer sequence and functional similarity and are generally still conserved at least between multiple phyla.

History of Kinase Classification

This kinase classification was first published by Manning and colleagues from Sugen in 2002 in papers covering the human kinome [1] and the yeast, worm, and fly kinomes [2]. This scheme was largely built on and early 1995 scheme by Hanks and Hunter [3], extending it from 5 groups, 44 families and 51 subfamilies to 9 groups, 134 families and 196 subfamilies.

The classification has been continuously revised since then, largely by the Manning lab at the Salk Institute. A few notable changes are:

• The Atypical group used to cover all kinases not in the ePK superfamily. This has now been split into PKL (kinases that share a fold with ePKs but are in different superfamilies), HisK (histidine kinase fold kinases), NDK (nucleoside diphosphate kinases), and the remaining Atypical kinases that belong to several structural folds that are not known to generally have kinase activity.

• Extensive additional subfamilies have been added for non-human species.

• Additional subfamilies have been created for kinases that have distinct orthologs across multiple phyla

Additional Notes

• Several publications use this classification but have mixed up the classification levels, in particular referring to groups as families or families as subfamilies.

• The scheme is not completely monophyletic, and relies on several "left-over" groups to simplify the classification: in particular, Atypical includes many unrelated kinases; the PKL group contains all PKL-fold kinases that are not ePKs, and the Other group includes all ePKs that do not fit into any other group.

References

1. Manning G, Whyte DB, Martinez R, Hunter T, and Sudarsanam S. The protein kinase complement of the human genome. Science. 2002 Dec 6;298(5600):1912-34. DOI:10.1126/science.1075762 |
2. Manning G, Plowman GD, Hunter T, and Sudarsanam S. Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci. 2002 Oct;27(10):514-20. DOI:10.1016/s0968-0004(02)02179-5 |
3. Hanks SK and Hunter T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 1995 May;9(8):576-96.