TGF-β Superfamily of Proteins
The Transforming Growth Factor-beta (TGF-β) superfamily of proteins is a large set of secreted, extracellular ligands that play several roles in a huge number of biological processes. Bone Morphogenetic Proteins (BMPs) are a large subdivision of the over 40 member strong superfamily along with Growth and Differentiation Factor (GDF), Activin and Inhibin, Nodal, Mullerian Inhibiting Substance (MIS), Glial cell line-Derived Neurotrophic Factor (GDNF) and TGF-β subclasses (Derynck & Miyazono 2008; Vitt et al. 2001). The TGF-β superfamily are involved in many developmental processes including playing pivotal roles in proliferation, differentiation, apoptosis, adhesion, migration and extra-cellular matrix (ECM) production that help the coordination of the organization of tissues and organs (Derynck & Akhurst 2007; Kitisin et al. 2007; Dennler et al. 2002).
The diversity of responses depends on the genetic makeup and environment of the target cell. In adult tissue, the TGF-β superfamily are directly involved in the wound healing process, reproduction and immune response (Schiller et al. 2004; Luo et al. 2010; Letterio & Roberts 1998). The superfamily ligands are characterized by 6 conserved cysteine residues and are encoded by 42 open reading frames in humans (Walsh et al. 2010; Lander et al. 2001).
TGF-β superfamily structure
The general structure of TGF-β superfamily members is that of a ‘butterfly’ made up of two subunits related by twofold rotational symmetry around a connecting intermolecular disulfide bond through a cysteine knot. However, throughout the superfamily there is significant structural variability which is currently not well understood in how this affects function (Kwiatkowski et al. 2014). TGF-β signalling is initiated by the association of a TGF-β ligand to two type I and two type II receptors at the cell surface. The TGF-β are transmembrane serine threonine kinases and once the ternary signalling complex is formed the type II receptor phosphorylates the type I receptor kinase domain which allows signal propagation to target genes occurs through either the trans-phosphorylation of RSMADs or sma and mothers against decepentaplegic (SMAD) independent means (crosstalk with other pathways including RAS, Hedgehog, Notch, WNT, IFN, TFN Engineering BMP Interactions 4 and PI3K-AKT) (Akhurst & Hata 2012; Dennler et al. 2002).
TGF-β superfamiy dysfunction
Dysfunction of the TGF-β superfamily signalling pathways play significant roles in many pathologies including fibroses, skeletomuscular diseases, autoimmune diseases, vascular disorders and cancers (Gordon & Blobe 2008). Due to the variety and breadth of signalling, the TGF-β superfamily is a major subject for engineering and development to provide potential therapeutic utility (Kwiatkowski et al. 2014). Indeed, BMP-2 and BMP-7 have already been approved by the Food and Drug Administration (FDA) and utilized as therapeutics in specific orthopaedic applications (Khan & Lane 2004; Senta et al. 2009).