Overview
Receptor serine/threonine kinases (RSTK), EC 2.7.11.30, respond to particular cytokines, the transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) families, and may be divided into two subfamilies on the basis of structural similarities. Agonist binding initiates formation of a cell-surface complex of type I and type II RSTK, possibly heterotetrameric, where both subunits express serine/threonine kinase activity. The type I receptor serine/threonine kinases are also known as activin receptors or activin receptor-like kinases, ALKs, for which a systematic nomenclature has been proposed (ALK1-7). The type II protein phosphorylates the kinase domain of the type I partner (sometimes referred to as the signal propagating subunit), causing displacement of the protein partners, such as the FKBP12 FK506-binding protein FKBP1A (P62942) and allowing the binding and phosphorylation of particular members of the Smad family. These migrate to the nucleus and act as complexes to regulate gene transcription. Type III receptors, sometimes called co-receptors or accessory proteins, regulate the signalling of the receptor complex, in either enhancing (for example, presenting the ligand to the receptor) or inhibitory manners. TGFβ family ligand signalling may be inhibited by endogenous proteins, such as follistatin (FST, P19883), which binds and neutralizes activins to prevent activation of the target receptors.
Endogenous agonists, approximately 30 in man, are often described as paracrine messengers acting close to the source of production. They are characterized by six conserved cysteine residues and are divided into two subfamilies on the basis of sequence comparison and signalling pathways activated, the TGFβ/activin/nodal subfamily and the BMP/GDF (growth/differentiation factor)/MIS (Müllerian inhibiting substance) subfamily. Ligands active at RSTKs appear to be generated as large precursors which undergo complex maturation processes [2]. Some are known to form disulphide-linked homo- and/or heterodimeric complexes. Thus, inhibins are α subunits linked to a variety of β chains, while activins are combinations of β subunits.
How to cite this family page
Database page citation:
Receptor serine/threonine kinase (RSTK) family. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=303.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Catalytic receptors. Br J Pharmacol. 176 Suppl 1: S247-S296.
A number of endogenous inhibitory ligands have been identified for RSTKs, including BMP-3 (BMP3, P12645), inhibin α (INHA, P05111), inhibin βC (INHBC, P55103) and inhibin βE (INHBE, P58166).
An appraisal of small molecule inhibitors of TGFβ and BMP signalling concluded that TGFβ pathway inhibitors were more selective than BMP signalling inhibitors [3]. The authors confirmed the selectivity of TGF-beta RI inhibitor III to inhibit TGFβ signalling through ALK4, ALK5, ALK7 [1]. Dorsomorphin inhibits BMP signalling through ALK2 and ALK3, it also inhibits AMP kinase [4].
Smads were identified as mammalian orthologues of Drosophila genes termed “mothers against decapentaplegic” and may be divided into Receptor-regulated Smads (R-Smads, including Smad1, Smad2, Smad3, Smad5 and Smad8), Co-mediated Smad (Co-Smad, Smad4) and Inhibitory Smads (I-Smad, Smad6 and Smad7). R-Smads form heteromeric complexes with Co-Smad. I-Smads compete for binding of R-Smad with both receptors and Co-Smad.