Difference between revisions of "Evolution of tyrosine kinases"

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===Tyrosine Kinases===
 
===Tyrosine Kinases===
 
These are the kinases of the TK group. They are defined by their overall sequence similarity to other TKs, but also by two key motifs that differ in sequence from those of Ser/Thr kinases. In the activation loop, the canonical HrDlKPEN is changed to HrD[IVLM]AaRN (HrdLRaaN in vertebrate Srcs) and the Y preceding the APE motif is changed to a W. The overall sequences are most similar to the diverse TKL group, from which they may have emerged. The first clear TKs are seen in holozoans - the unicellular protists intermediate between fungi and animals - though possible TKs have also been seen in a few other basal lineages.
 
These are the kinases of the TK group. They are defined by their overall sequence similarity to other TKs, but also by two key motifs that differ in sequence from those of Ser/Thr kinases. In the activation loop, the canonical HrDlKPEN is changed to HrD[IVLM]AaRN (HrdLRaaN in vertebrate Srcs) and the Y preceding the APE motif is changed to a W. The overall sequences are most similar to the diverse TKL group, from which they may have emerged. The first clear TKs are seen in holozoans - the unicellular protists intermediate between fungi and animals - though possible TKs have also been seen in a few other basal lineages.
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===TKL kinases===
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This group is most similar to TKs in sequence and structure, but most members are known to be serine/threonine kinases. However, there is emerging evidence than in plants and Dictyostelium, several may act as tyrosine-specific or dual-specificity kinases, and in these lineages the group is both expanded and frequently part of transmembrane receptors (within animals, the only receptor TKLs are the TGFb receptors).
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===Dual-specificity kinases===
 
===Dual-specificity kinases===

Revision as of 01:15, 8 September 2010

Tyrosine phosphorylation is relatively rare (relative to pSer and pThr), but is critical in transduction of extracellular signals and a major target for cancer and other therapies. Most tyrosine kinases come from the TK group, which is specific to multicellular animals and close unicellular relatives (holozoans), but it is now emerging that extensive tyrosine phosphorylation predates the animals, and can be mediated by several other sources.

Tyrosine Kinases

These are the kinases of the TK group. They are defined by their overall sequence similarity to other TKs, but also by two key motifs that differ in sequence from those of Ser/Thr kinases. In the activation loop, the canonical HrDlKPEN is changed to HrD[IVLM]AaRN (HrdLRaaN in vertebrate Srcs) and the Y preceding the APE motif is changed to a W. The overall sequences are most similar to the diverse TKL group, from which they may have emerged. The first clear TKs are seen in holozoans - the unicellular protists intermediate between fungi and animals - though possible TKs have also been seen in a few other basal lineages.

TKL kinases

This group is most similar to TKs in sequence and structure, but most members are known to be serine/threonine kinases. However, there is emerging evidence than in plants and Dictyostelium, several may act as tyrosine-specific or dual-specificity kinases, and in these lineages the group is both expanded and frequently part of transmembrane receptors (within animals, the only receptor TKLs are the TGFb receptors).


Dual-specificity kinases

These can phosphorylate on tyrosine as well as serine and threonine. Many kinases may be capable of dual-specificity in particular circumstances, but here are the classes that have been well studied.

MEK (MAP2K)

These phosphorylate the activation loops of MAPKs on both the T and the Y of a conserved TxY motif. These sites are conserved and have been seen to be phosphorylated in plants, fungi and animals.

DYRK

This family also autophosphorylates on tyrosine (the name stands for "Dual specificity tYrosine Regulated Kinase"). This phosphorylation is apparently constitutive and happens once as the protein is folding. No other tyrosine substrate for DYRK has been found.

CK2

Reviewed in Medline: 12396231


Wee1

Not really a dual-specificity kinase, but rather a divergent S/T-like kinase whose only known substrate is a tyrosine. Wee1 phosphorylates the kinase CDC2 during cell cycle in all eukaryotes. Phosphorylation is inhibitory, within the ATP-binding G-loop (GxGxYG, with the Y conserved in many other CMGC kinases, while usually F in most other groups).

TESK

TKL

This group is most similar to the TKs in sequence and structure, but is found in most eukaryotic lineages. In plants and Dictyostelium there is strong evidence that TKLs can act as tyrosine kinases. In both cases, the family is expanded, and many are found as transmembrane receptors, like most TKs are. In Dictyostelium, six TKLs have been shown to phosphorylate Tyr (Goldberg et al., 2006) and four others are fused to SH2 domains, suggesting that they do likewise.


Homologs of metazoan GSK3, c-Cbl (no pTyr sites conserved!) and STAT proteins that are regulated by Tyr phosphorylation have conserved these phosphorylation sites in Dictyostelium (unpublished), and both STAT and GSK3 have been shown to be Tyr-phosphorylated by Dictyostelium TKL kinases, suggesting that these control mechanisms are ancient, and that the later invention of TKs may have displaced TKLs from this role and these specific substrates.

[need to fill in more specific details here - the names of the kinases, and which phosphorylate which]

In plants, several TKLs (IRAKs) have been implicated in tyrosine phosphorylation, and many IRAKs have tyrosines in their activation loop, at least one has been seen to be phosphorylated (Steve Briggs, unpublished).

In metazoans, TKLs include homologs of the plant IRAKs, as well as the only Ser/Thr receptor kinases, the STKR family (TGFb and activin receptors). IRAK4 is phosphorylated on the Y of the YMAPE motif, and it's structure was noted as being similar to that of TKs (ref), while TGFbR1 was seen to autophosphorylate on three tyrosine residues when expressed as a cytoplasmic-only domain in bacteria or insect cells (Lawler et al), including on the YMAPE tyrosine.