The transforming growth factor-β superfamily of receptors

Abstract

The transforming growth factor-β (TGF-β) superfamily of receptors comprises two groups of transmembrane serine-threonine kinase receptors, so called type I, and type II receptors, that are activated following engagement by members of the TGF-β superfamily of ligands. These events specify diverse downstream responses that are differentially regulated by controlling access and activation of the ligands, their receptors and downstream substrates in different cell types. The purpose of this review is to describe the biochemical properties of these receptors, focusing specifically on the mechanisms regulating receptor/ligand interactions and activation in mammalian cells.

Introduction

The transforming growth factor-β (TGF-β) superfamily consists of a large family of structurally related polypeptide growth factors. These can be phylogenetically divided into two main groups: the TGF-β/Activin and bone morphogenetic protein (BMP)/growth and differentiation factor (GDF) branches. These can be sub-divided into several related sub-groups based on their sequence similarity and relationship to evolutionary conserved molecules in primitive organisms [1], [2], [3] (Table 1). Ligands are synthesized as large precursor molecules that undergo proteolytic cleavage, releasing the pro-domain from the active, receptor binding, carboxy-terminal region of the molecule. This intra-cellular cleavage event is regulated by the expression of subtilisin-like pro-protein convertases, SPC1/Furin and SPC4/PACE4 [4], [5]. The active, carboxy-terminal domains of these ligands have six intra-strand disulfide bonds that form a “cysteine knot” folding motif [6], [7], [8], [9], [10], [11]. With the exception of GDF3 and GDF9 [12], all of the remaining TGF-β superfamily members have a conserved seventh cysteine residue that is required to form covalently linked dimeric structures that interact with the ligand-binding extra-cellular domains of their respective receptors [11], [13], [14]. A variety of regulatory networks have been established to control access of these secreted ligands to their respective receptors. TGF-β and GDF8 are unique amongst this family of growth factors in that they are synthesized as inactive precursors, cleaved into mature and the latency associated peptides, which are non-covalently linked to the mature ligands, preventing binding to their respective receptors [15], [50]. In contrast, other members of the TGF-β superfamily are secreted as mature, active dimers that are inhibited locally through interactions with a variety of secreted antagonists including Noggin, Chordin, DAN/Cerberus family of proteins, Follistatin and Follistatin-related protein (FSRP) and Sclerosin [16].

The characteristic structural feature of the TGF-β superfamily of receptors is the three-finger toxin fold in the ligand-binding extra-cellular domain, a single trans-membrane and an intracellular serine-threonine kinase domain. These are divided into two groups, the types I and II receptors (Table 2). Distinction between the two receptor sub-types is based on sequence conservation in their kinase domains and the presence of a glycine-serine rich juxta-membrane domain (the GS box) in the type I receptors which is critical for their activation (see below). The nomenclature for the types I and II receptors is somewhat confusing. For simplicity I have referred to the type I receptors by a common nomenclature, the Activin-like kinases (Alks) [17], [18], and the type II receptors according to their dominant ligand interactions. Type I receptors are classified according to sequence similarities into three main groups: the Alk5 group which includes the TGF-β type I receptor Alk5, the Activin receptor Alk4 and the Nodal receptor Alk7; the Alk3 group comprising the BMP type I receptors Alk3 and Alk6; and the Alk1 group Alk1 and Alk2, which interact with different BMP/GDF and TGF-β/Activin family ligands. Type II receptors include the TGF-β type II receptor, TGF-β RII, the Activin and BMP/GDF type II receptors, Activin RII and RIIB, the BMP/GDF type II receptor, BMP RII, and the Mullerian inhibitory substance (MIS) type II receptor, MIS RII. Germ line mutations have been made for the majority of these receptors in mice [19], [20], [21], and demonstrate that these signaling pathways play critical roles in the regulation of diverse biological functions. In addition, there is increasing evidence that a number of these pathways are defective in a range of acquired and inherited human diseases [22], [23], [24], [25], [26]. The purpose of this review is to describe the biochemical properties of the TGF-β superfamily receptors in mammalian cells, focusing specifically on receptor–ligand interactions, accessory receptors and receptor activation. The reader is referred to a series of reviews for a more detailed description of the functional properties of this these events in vivo [19], [20], [21], [22], [23], [25].