TGF-beta 2 (transforming growth factor beta 2) is one of three closely related mammalian members of the large TGF-beta superfamily that share a characteristic cysteine knot structure (1-7). TGF-beta 1, -2 and -3 are highly pleiotropic cytokines proposed to act as cellular switches that regulate processes such as immune function, proliferation and epithelial- mesenchymal transition (1-4). Each TGF-beta isoform has some non-redundant functions; for TGF-beta 2, mice with targeted deletion show defects in development of cardiac, lung, craniofacial, limb, eye, ear and urogenital systems (2).
Human TGF-beta 2 cDNA encodes a 414 amino acid (aa) precursor that contains a 19 aa signal peptide and a 395 aa proprotein (8). A furin-like convertase processes the proprotein to generate an N-terminal 232 aa latency-associated peptide (LAP) and
a C-terminal 112 aa mature TGF- beta 2 (8, 9). Disulfide-linked homodimers of LAP and TGF-beta 2 remain non-covalently associated after secretion, forming the small latent TGF-beta 1 complex (8-10). Covalent linkage of LAP to one of three latent TGF-beta binding proteins (LTBPs) creates a large latent complex that may interact with the extracellular matrix (9, 10).
TGF-beta is activated from latency by pathways that include actions of the protease plasmin, matrix metalloproteases, thrombospondin 1 and a subset of integrins (10). Mature human TGF-beta 2 shows 100% aa identity with porcine, canine, equine and bovine TGF-beta 2, and 97% aa identity with mouse and rat TGF-beta 2. It demonstrates cross-species activity (1). TGF-beta 2 signaling begins with binding to a complex of the accessory receptor betaglycan (also known as TGF-beta RIII) and a type II ser/thr kinase receptor termed TGF-beta RII. This receptor then phosphorylates and activates another ser/thr kinase
receptor, TGF-beta RI (also called activin receptor-like kinase (ALK) -5), or alternatively, ALK-1. The whole complex phosphorylates and activates Smad proteins that regulate transcription (3, 11, 12). Use of other signalin.
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