TGF- beta 1 (Transforming Growth Factor beta 1) and the closely related TGF-beta 2 and -beta 3 are
members of the large TGF-beta superfamily. TGF beta proteins are highly pleiotropic cytokines with
distinct, but overlapping, activities regulating processes such as immune function, proliferation,
and epithelial mesenchymal transition (1-3). Almost all cells can produce TGF-beta 1, and a
particularly high concentration is found in platelets (1-4). Human TGF-beta 1 cDNA encodes a
390 amino acid (aa) precursor that contains a 29 aa signal peptide and a 361 aa proprotein (2).
A furin-like convertase processes the proprotein within the trans-Golgi to generate an
N-terminal 249 aa latency-associated peptide (LAP) and a C-terminal 112 aa mature TGF- beta 1
(2, 3, 5). Disulfide-linked homodimers of LAP and TGF-beta 1 remain non-covalently associated after
secretion, forming the inactive small latent TGF-beta 1 complex (5-12). 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 (3, 5-7, 13). TGF-beta activation from latency is controlled both
spatially and temporally by multiple pathways that may include the actions of proteases such as
plasmin, MMP-2 or MMP-9, adhesion through integrins such as alpha v beta 6 and alpha v beta 8, and/or
interaction with Thrombospondin-1 (3, 5, 7, 12-14).
Recombinant TGF-beta 1 LAP is capable of complexing with and inactivating all other human TGF-beta
isoforms and those of most other species (15). The TGF-beta 1 LAP is associated in vivo with TGF-beta 1
and binds >98% of the TGF-beta 1 in circulation (16). Its circulating concentration correlates with
that of total TGF-beta 1, making LAP a convenient surrogate in the measurement of TGF-beta 1 (16). LAP
is accessible for antibody recognition whether or not TGF-beta 1 is bound. In contrast, latent TGF-beta 1
is surrounded by a LAP "straightjacket", altering its conformation and sequestering it from
recognition by receptors or antibodies (4, 8). Acid dissociation of TGF-beta 1 from its LAP is thus
required to assay total TGF-beta 1 (4, 16). The LAP portion of human TGF-beta 1 shares 91%, 92%, 85%,
86% and 88% aa identity with porcine, canine, mouse, rat, and equine TGF-beta 1 LAP, respectively,
while the mature human TGF-beta 1 portion shares 100% aa identity with porcine, canine, and
bovine TGF-beta 1, and 99% aa identity with mouse, rat, and equine TGF-beta 1. Assays for TGF-beta 1 LAP
may therefore be more species-specific than assays for mature TGF-beta 1. Assay of human LAP is an
especially convenient way to eliminate interference from bovine serum TGF-beta 1 and its LAP in
tissue culture media.
Deletion of the mouse TGF-beta 1 gene is lethal, either due to defective prenatal hematopoiesis and
endothelial differentiation, or to postnatal overwhelming inflammation (17). Mutations within
the human TGF-beta 1 LAP are associated with Camurati-Engelmann disease, a rare sclerosing bone
dysplasia characterized by inappropriate presence of active TGF-beta 1 (7-9, 18). LAP on the surface
of immature dendritic cells promotes differentiation and survival of regulatory T cells (Treg) while
inhibiting Th1 cell differentiation (19). Latent TGF-beta 1 is also expressed on the surface of Treg,
where it is immobilized by binding of LAP to the alternate latent TGF binding protein, GARP, and
contributes to the immunosuppressive role of Treg (14, 20-23).