The transforming growth factors-beta constitute a family ofmulti-functional cytokines that regulate cell growth and differentiation []. Many cells synthesise TGF-beta, and essentially all have specific receptors for this peptide []. TGF-beta regulates the actions of many other peptide growth factors and determines a positive or negative direction of their effects. The protein functions as a disulphide-linked homodimer. Its sequence is characterised by the presence of several C-terminal cysteine residues, which form interlocking disulphide links arranged in a knot-like topology. A similar "cystine-knot"arrangement has been noted in the structures of some enzyme inhibitors and neurotoxins that bind to voltage-gated Ca2+ channels, although the precise topology differs.The three-dimensional structures of several members of the TGF-beta super-family have been deduced [, , ]. TGF-beta genes are expressed differentially, suggesting that the various TGF-beta species may have distinct physiological roles in vivo.The solution structure of human TGF-beta 1 was determined using multinuclear magnetic resonance spectroscopy with hybrid distance geometry/simulated annealing []. The structure shows a high degree of similarity to that of TGF-beta 2, but with notable differences in structure and flexibility. Examination of TGF-beta 1 mRNA levels in adult murine tissues indicates that expression is predominant in spleen, lung and placenta []. TGF-beta 1 is believed to play important roles in pathologic processes.
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.Integrin Beta-6 associates with Alpha-V to form the receptor for the TGFB1 latency-associated peptide (LAP) []. Cells expressing this integrin combination induce spatially restricted activation of TGFB1, while mice lacking the integrin display exaggerated inflammation and are protected from pulmonary fibrosis.
