Kinase Group TKL

Kinase Classification: Tyrosine Kinase-Like (TKL) Group

The TKL group is the most recently-defined and most diverse of the standard kinase groups. Families within the group are relatively weakly related to each other, and all are also similar to members of the TK (Tyrosine Kinase) group, though they generally lack the TK-specific motifs of the TK group. Over half of plant kinomes is made of TKL kinases, and they include receptor kinases and possible tyrosine-specific kinases in other lineages.

Evolution

The TKL group is found in almost all eukaryotes, including Dictyostelium, plants, and vertebrates. However, it is conspicuously absent from the yeast (S. cerevisiae) kinome. There are large expansions in Dictyostelium (in families that may act as tyrosine kinases, including receptor tyrosine kinases) and in plants. The similarity in sequence between TKL and TK suggests that the TK group may have emerged from the more ancient TKL kinases.

Families

There are eight major TKL families in animals:

MLK

Mixed Lineage Kinases, named after their sequence similarity to both tyrosine and serine/threonine kinases. Act frequently in MAPK cascades, as MAP4K kinases.

MLKL

Pseudokinase involved in necroptosis, a form of programmed cell death, along with the RIPK kinases.

RAF

The Raf family also acts as MAP4K, typically coupling ras-like small GTPases to growth response signals of the Erk-MAPK pathway.

STKR

These Serine Threonine Kinase Receptors include the TGFb and activin receptors. These are cell surface receptors which are dimers, with one member each from the two subfamilies within this family.

LRRK

Leucine Rich Repeat Kinases, named after their domain structure. Little studied, outside of Dictyostelium (where they are known as Roco kinases). LRRK2 has been recently implicated as a genetic cause of Parkinson's Disease.

LISK

Consists of two subfamilies which are closely related in sequence, though not by any known common function. These are the LIMK (LIM domain Kinase) and TESK (Testis Expressed Serine Kinase) subfamilies.

IRAK

IL1 Receptor Associated Kinase. Homologs of Drosophila pelle, these associate with TRAFs and signal though the NFkB and Jnk pathways. What appear to be plant orthologs account for the vast majority of plant kinases, with over 500 members in higher plant genomes, most of which are receptors, possibly analogous to the receptor tyrosine kinases of metazoans.

RIPK

Receptor Interacting Protein Kinase. Couples TNF receptors to NF-kB signaling.

Several other minor TKL families are defined, including 7 within the Dictyostelium kinome, the animal specific TKL-Sp1, and many others. In fact, TKL is the most polymorphic group with a large number of lineage-specific expansions and kinases that are difficult to classify. Several 'leftover' TKLs are placed in the |TKL-Unique pseudofamily.