Kinase Family STKR

Kinase Classification: Group TKL: Family STKR

Serine Threonine Kinase Receptors (STKR) are the only serine-threonine specific cell surface receptor kinases in animals, and transduce developmental and growth signals through heterodimers. They consist of two subfamilies, STKR1 (Type I) and STKR2 (Type II), which form obligate heterodimers in which the Type II receptor typically phosphorylates the Type I receptor, which then phosphorylates substrate proteins.

The STKR family has the following subfamilies:

Evolution

STKRs are found only in metazoans. The are first seen in sponges, where evidence of Type I and Type II receptors is already clear. They expand in several lineages, with 12 members in humans that transduce signals from TGFbeta superfamily members including activins and bone morphogenetic proteins. While they are the only ser/thr receptor kinases in animals, other TKL group kinases are enriched for receptor activity in other lineages, including plants and Dictyostelium.

Domain Structure

These have a typical single-pass transmembrane architecture, typically with an activin recpetor domain on the external face and the kinase domain on the internal face. Some do not have a detectable activin receptor domain.

Are STKRs tyrosine kinases?

Despite there name, there is some weak published evidence that STKRs may act as tyrosine kinases. In a 1998 paper Lawler et al [1] reported that the kinase domain of human TGFbR2 purified in insect cells could autophosphorylate on three tyrosines within the kinase domain: Y259, Y336, and Y424. No phosphorylation was seen in a kinase-dead construct. The construct could also tyrosine phosphorylate histone H2B and the synthetic substrate poly(Glu-Tyr). Human TGFbR2 was also shown to be weakly tyrosine phosphorylated in vivo, and this was lost when transfecting a kinase-dead construct. A change of all three tyrosine to phenylalanine blocked kinase activity, though this is probably due to the conserved nature of Y424, which is part of the YMAPE motif, rather than it being phosphorylated. The other two residues are more weakly phosphorylated, and neither is well conserved in orthologs of TGFbR2 or other family members, suggesting that such phosphorylation may not be functionally critical or evolutionarily conserved. Some phosphorylation of the YMAPE motif has been seen in Alk1 and Alk4 (Phosphosite), but it is not known if this is functionally relevant.

Another paper from the Derynck lab [2] demonstrated that an STKR1 family member, human TGFbR1 could autophosphorylate on serine, and could transphosphorylate the adaptor protein ShcA on both serine and tyrosine, leading to Erk cascade activation.

References

1. 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 |
2. Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, Smith SM, and Derynck R. TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J. 2007 Sep 5;26(17):3957-67. DOI:10.1038/sj.emboj.7601818 |
3. 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 |
4. 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 |