The mouse, rat, porcine and canine TGF-beta 1 cDNAs encode a 390 amino acid (aa) residue
precursor that contains a 29 aa signal peptide and a 361 aa pro-protein. The pro-protein for
each species is proteolytically processed via a furin-like convertase to generate an N-terminal
249 aa latency-associated peptide (LAP), and a C-terminal 112 aa mature TGF-beta 1 (4-9). Both
LAP and mature TGF-beta 1 exist as disulfide-linked homodimers. After proteolytic cleavage and
secretion, the two homodimers remain non-covalently associated as the small latent TGF-beta 1
complex. In most cell types, this complex is also covalently linked via LAP to a latent TGF-beta
binding protein (LTBP). This creates a secreted, large latent complex. The TGF-beta 1 present in
either the small or the large latent complex is not available for TGF-beta receptor binding and
activation, and is, therefore, latent. Whereas LAP is both necessary and sufficient to confer
latency to TGF-beta 1, LTBP facilitates the proper folding and secretion of the small latent complex.
LTBP is also a structural component of the extracellular matrix and directs the localization of
the latent complex to the extracellular matrix (10-15). To date, four LTBPs that share multiple
EGF-like, LTBP- and fibrillin-specific domains have been cloned. Three of the four LTBPs (#1,
3, and 4) have been shown to bind the small latent complexes of all TGF-beta isoforms (16).
Activation of the latent TGF-beta complex is an important step that regulates TGF-beta function
in vivo. Multiple activation mechanisms have been identified. These involve proteasedependent (plasmin and matrix metalloprotease) and protease-independent (binding of LAP
to thrombospondin 1 or a subset of integrins) pathways (5, 15, 17-21). Mature mouse TGF-beta 1
shows 100% aa sequence identity to mature rat TGF-beta 1 (6, 7), and both rat and mouse TGF-beta 1
show 99% aa sequence identity with mature porcine, human, and canine TGF-beta 1 (4, 9, 22).
Mature porcine TGF-beta 1 shows absolute identity to both mature human and canine TGF-beta 1.
The signalling high-affinity receptor for TGF-beta 1 is a heteromeric complex consisting of a type I
(TGF-beta RI) and a type II (TGF-beta RII) transmembrane serine/threonine kinase receptor. TGF-beta RII is
a constitutively active kinase. Upon binding TGF-beta 1, it phosphorylates and activates the TGF-beta
RI. In turn, TGF-beta RI phosphorylates and activates Smad proteins that regulate transcription.
TGF-beta RI, alternatively named activin receptor-like kinase (ALK-5), is present in almost all cell
types. Two other type I receptors, ALK-1 and ALK-2 have also been implicated as alternative
partners for TGF-beta RII in the TGF-beta signalling receptor complex. Besides the type I and type
II receptors, accessory receptors including the type III receptor, TGF-beta RIII (also known as
betaglycan), and endoglin, which modulate TGF-beta responses, have been identified (2, 23-26).
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