Mini ReviewThe transforming growth factor-β superfamily of receptors
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].
Section snippets
Receptor–ligand interactions
The TGF-β family of ligands have different affinities for different types I and II receptor combinations (Table 2), although the basic paradigm by which TGF-β family ligands interact with and activate these receptors has been largely established from studies of TGF-β [44], [52]. TGF-β binds to the constitutively active TGF-β type II receptor, TGF-β RII, which then recruits the TGF-β type I receptor Alk5, resulting in trans-phosphorylation of the type I receptor and activation of downstream
Accessory receptors
Despite the complexity of the receptor–ligand interactions, it is apparent that other cell surface proteins interact with and maybe required for proper signaling. Some of these have been cloned and characterized and will be discussed below, while others have been identified from ligand–receptor cross-linking studies in certain cell types and are of uncertain significance [70], [71], [72].
Receptor activation
Unlike receptor tyrosine kinases in which activation is induced by phosphorylation of a central structural element within the kinase domain [90], activation of type I TGF-β receptors results from serine phosphorylation by the type II receptor kinase within the GS box immediately upstream of the catalytic domain [42], [44], [48], [52], [53]. These phosphorylation events are associated with a conformational change in the GS box which normally forms an inhibitory wedge in the kinase domain of the
Perspectives
While considerable advances have been made in our understanding of the basic biochemistry of TGF-β receptor family over the last decade, these findings have probably raised more questions than they have answered. The large number of TGF-β ligands, the plasticity of receptor usage and the diversity of downstream pathways regulated by these receptors, along with the increasing apparent role of TGF-β superfamily signaling in the pathogenesis of human disease, secures the prominence of future
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