Evolution of tyrosine kinases

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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 catalytic 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.

Despite being usually linked only to multicellular animals, TK group kinases have also been found in choanoflagellates, the unicellular closest relatives of the animals [1]. Several families of cytoplasmic kinases (Src, Abl, Tec, Csk) are conserved between metazoans and choanoflagellates, but the many receptor tyrosine kinases had no specific relationship to animals RTKs. Analysis of the earliest-branching metazoan, the sponge Amphimedon queenslandica, shows the emergence of most animal-style RTK families, though in several cases metazoan-style kinase domains are coupled to novel extracellular regions [2].

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, but most TKs are receptors). In Dictyostelium, six TKLs have been shown to phosphorylate Tyr [3] and four others are fused to SH2 domains, suggesting that they do likewise. Dictyostelium homologs of metazoan c-Cbl, STAT and GSK3 that are regulated by tyrosine phosphorylation are also tyrosine phosphorylated in Dictyostelium (and the GSK3 and STAT conserve the exact same site), 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. (See: Tyrosine Phosphorylation in Dictyostelium).

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 (to be filled in).

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 (at the end of the activation segment, though distant from the typical TK autophosphorylation sites), and its structure was noted as being similar to that of TKs (ref), while a catalytic fragment of TGFbR2 was seen to autophosphorylate on three tyrosine residues when expressed as a cytoplasmic-only domain in bacteria or insect cells [4]. One of these positions is the YMAPE tyrosine, a position that is also phosphorylated by Src and appears to regulate kinase activity [5]. The TGFbR1 structure also shows some characteristics of tyrosine kinases, suggestiing that it might also be able to phosphorylate tyrosine [6].

Dual-specificity kinases

Many other kinase groups have kinases with reported Ser/Thr and Tyr kinase activity, and have been labeled "Dual Specificity Kinases". Some are very well understood, while others are claimed based on single reports, or from only in vitro studies. We've moved the review of these to a separate page: Dual-Specificity Kinases.

Plant tyrosine kinases

See Plant tyrosine kinases.


  1. Manning G, Young SL, Miller WT, and Zhai Y. The protist, Monosiga brevicollis, has a tyrosine kinase signaling network more elaborate and diverse than found in any known metazoan. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9674-9. DOI:10.1073/pnas.0801314105 | PubMed ID:18621719 | HubMed [Manning]
  2. Srivastava M, Simakov O, Chapman J, Fahey B, Gauthier ME, Mitros T, Richards GS, Conaco C, Dacre M, Hellsten U, Larroux C, Putnam NH, Stanke M, Adamska M, Darling A, Degnan SM, Oakley TH, Plachetzki DC, Zhai Y, Adamski M, Calcino A, Cummins SF, Goodstein DM, Harris C, Jackson DJ, Leys SP, Shu S, Woodcroft BJ, Vervoort M, Kosik KS, Manning G, Degnan BM, and Rokhsar DS. The Amphimedon queenslandica genome and the evolution of animal complexity. Nature. 2010 Aug 5;466(7307):720-6. DOI:10.1038/nature09201 | PubMed ID:20686567 | HubMed [Srivastava]
  3. Goldberg JM, Manning G, Liu A, Fey P, Pilcher KE, Xu Y, and Smith JL. The dictyostelium kinome--analysis of the protein kinases from a simple model organism. PLoS Genet. 2006 Mar;2(3):e38. DOI:10.1371/journal.pgen.0020038 | PubMed ID:16596165 | HubMed [Goldberg]
  4. Lawler S, Feng XH, Chen RH, Maruoka EM, Turck CW, Griswold-Prenner I, and Derynck R. The type II transforming growth factor-beta receptor autophosphorylates not only on serine and threonine but also on tyrosine residues. J Biol Chem. 1997 Jun 6;272(23):14850-9. DOI:10.1074/jbc.272.23.14850 | PubMed ID:9169454 | HubMed [Lawler]
  5. Galliher AJ and Schiemann WP. Src phosphorylates Tyr284 in TGF-beta type II receptor and regulates TGF-beta stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Res. 2007 Apr 15;67(8):3752-8. DOI:10.1158/0008-5472.CAN-06-3851 | PubMed ID:17440088 | HubMed [Galliher]
  6. Huse M, Chen YG, Massagué J, and Kuriyan J. Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12. Cell. 1999 Feb 5;96(3):425-36. DOI:10.1016/s0092-8674(00)80555-3 | PubMed ID:10025408 | HubMed [Huse]
All Medline abstracts: PubMed | HubMed