Kinase classification

While most kinases share a common catalytic domain, sequence analysis shows that there are major variations on this domain, with distinct and ancient functions. To help deal with the diversity of kinases and map groups of kinases across large evolutionary distances, we developed a hierarchical classification: all kinases are assigned to a group, which consists of many families, and some families are divided into multiple subfamilies. Here we outline the 10 groups of protein kinases. Alternative classifiction schemes can include classification by function or by inhibitor binding profiles, though these are hampered by the multiple biological functions of many kinase families, and the idiosyncratic binding of many inhibitors.

The following classification applies to eukaryotic protein kinases (ePKs). Other kinases have the same Protein Kinase-Like (PKL) fold, and include protein and small molecule kinases. Yet other kinases have completely different catalytic folds and mechanisms, including most kinases that act as part of small molecule metabolism.

How the classification was made

Kinases were first clustered by sequence similarity in the kinase domain, and additional information from domains outside of the catalytic domain, from evolutionary conservation, and from known functions was added. The result is a hybrid classification, in which no criterion is universally satisfied, but aims to be of practical use to a range of kinase interests. The classification grows as new kinomes are sequenced. In particular, several new subfamilies have been added for kinases that are conserved between multiple phyla.

AGC

Named after the Protein Kinase A, G, and C families (PKA, PKC, PKG), this group contains many core intracellular signaling kinases which are modulated by cyclic nucleotides, phospholipids and calcium.

CMGC

Named after another set of families (CDK, MAPK, GSK3 and CLK), this group has a diversity of functions in cell cycle control, MAPK signaling, splicing and other unknown functions.

CAMK

Best known for the Calmodulin/Calcium regulated kinases (CAMK) in CAMK1 and CAMK2 families, this also has several families of non-calcium regulated kinases.

CK1

A small but ancient family. Originally known as Casein Kinase 1 (from a biochemically assay with a non-physiological substrate), and now renamed to Cell Kinase 1.

Other

This group consists of several families, and some unique kinases that are clearly ePKs but do not fit into the other ePK groups.

STE

Homologs of the yeast STE7, STE11 and STE20 genes, which form the MAPK cascade, transducing signals from the surface of the cell to the nucleus.

Tyrosine Kinase (TK)

This group phosphorylates almost exclusively on tyrosine residues, as opposed to most other kinases that are selective for serine or threonine

Tyrosine Kinase-Like (TKL)

The group most similar to tyrosine kinases, but whose activities are generally on serine/threonine substrates.

RGC

Receptor Guanylate Cyclases. This small group contains an active guanylate cyclase domain, which generates the cGMP second messenger, and a catalytically inactive kinase domain, which appears to have a regulatory function.

Atypical

Diverse group of kinases with little or no sequence similarity to ePKs. Several families have structural similarity to the ePK domain, and others have completely distinct, or undiscovered structures.

Other PKL Kinases

The PKL fold that includes protein kinases (ePKs) also has many other members, including lipid and sugar kinases, and others of unknown substrates. These are mostly bacterial, but a number are found in eukaryotes, including humans.