Dual-Specificity Kinases

Most protein kinases can phosphorylate on Serine or Threonine, and a distinct group (TKs) phosphorylates on tyrosine. Dual-specificty kinases are those than overall belong to Ser/Thr kinase groups, but can also phosphorylate on tyrosine. A few specific DSKs are very well known, though many others may have tyrosine kinase activity at a low level or under specific circumstances. Here is a summary of the reported dual-specificity kinase classes.

MEK/MAP2K

These kinases phosphorylate the activation loop of MAPK kinases, on both the T and Y of the TxY motif. Both phosphorylations are required for full activation of the MAPK. This motif is found in MAPKs throughout the eukaryotes, though some classes of MAPK lack the Y (e.g. Erk3, nmo) and are not activated by MEK kinases.

Wee1

Wee1 phosphorylates CDK1/CDC2 on a tyrosine in the ATP-binding loop. Wee1 is not known to have Ser/Thr substrates, but it's metazoan paralog, Myt1 has been reported to also phosphorylate CDK1 on an adjacent residue, T14 [1].

DYRK

Dyrk family kinases autophosphorylate on tyrosine, but transphosphorylate only on Ser/Thr. The autophosphorylation occurs while still attached to the ribosome, and is an intramolecular reaction [2]. Autophosphorylation occurs on a Y (YxY in DYRK1) in the activation loop which is almost absolutely conserved across all DYRK subfamilies.

GSK3

GSK3 is similar to DYRK in that an intramolecular autophosphorylation on an activation loop tyrosine occurs during maturation of the protein. In GSK3, the HSP90 chaperone is required to enable this phosphorylation [3]. After maturation, GSK3 is not seen to phosphorylate on tyrosine. GSK3 can be transphosphorylated by other tyrosine kinases, including MEK kinases in mammals and TKL kinases in Dictyostelium.

TKL group

To be added

TTK

To be added

CLK

The CLK family is related to DYRK, and members have been found to autophosphorylate and transphosphorylate on tyrosine in expression cloning in mammals, and in bacterial expression systems. However, in vivo substrates and physiological relevance of tyrosine phosphorylation is unclear. An activation loop tyrosine was seen to be phosphorylated in human CLK1 (http://www.phosphosite.org/proteinAction.do?id=2136&showAllSites=true), but this is only partially conserved (seen in CLK4 but is a F in CLK2/3 and also not conserved in invertebrates). At least one publication [] suggests that the tyrosine kinase activity might be an artefact of kinase overexpression or in vitro assays. The Drosophila homolog, Doa, failed to phosphorylate the model tyrosine substrate polyGlu/Tyr in vitro [4]

References

1. Fattaey A and Booher RN. Myt1: a Wee1-type kinase that phosphorylates Cdc2 on residue Thr14. Prog Cell Cycle Res. 1997;3:233-40. DOI:10.1007/978-1-4615-5371-7_18 |
2. Lochhead PA, Sibbet G, Morrice N, and Cleghon V. Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell. 2005 Jun 17;121(6):925-36. DOI:10.1016/j.cell.2005.03.034 |
3. Lochhead PA, Kinstrie R, Sibbet G, Rawjee T, Morrice N, and Cleghon V. A chaperone-dependent GSK3beta transitional intermediate mediates activation-loop autophosphorylation. Mol Cell. 2006 Nov 17;24(4):627-33. DOI:10.1016/j.molcel.2006.10.009 |
4. Lee K, Du C, Horn M, and Rabinow L. Activity and autophosphorylation of LAMMER protein kinases. J Biol Chem. 1996 Nov 1;271(44):27299-303. DOI:10.1074/jbc.271.44.27299 |