[Frontiers in Bioscience 7, d1231-1246, May 1, 2002]
HOMEOSTASIS OF EXTRACELLULAR MATRIX BY TGF-BETA AND LEFTY
Dept of OB/GYN and Fetomaternal Medicine, Stony Brook University, Stony Brook, NY 11794
FIGURES
Figure 1. Dendrogram of TGF-beta superfamily. Major families of TGF-beta superfamily include TGF-beta, Activin-inhibin, Nodal, BMP and lefty.
Figure 2. RXXR cleavage sites in TGF-beta and lefty. Both TGF-beta and lefty have signal peptide sequences and are secreted proteins. The processed form of TGF-beta is released by cleavage at a single cleavage site (RXXR). Furin is the convertase that cleaves TGF-beta at this cleavage site. In contrast, there are two such cleavage sites (RGKR and RHGR) in the lefty proteins, which causes release of two secreted proteins of 28 and 34 kD. PC5A cleaves lefty at RGKR site. The enzyme that cleaves lefty at the RHGR site has not yet been identified.
Figure 3. Signature motif of TGF-beta superfamily. The signature motif of TGF-beta family is comprised of a series of seven cysteine residues (boxed). Lefty and GDF are the only protein members that lack the third cysteine residue from the C terminus which leads to a dimerized form of the protein.
Figure 4. Dimerization of TGF-beta. The two dimensional structure of TGF-beta and a hypothetical 2-D structure of lefty are displayed. TGF-beta monomers dimerize by formation of a disulfide linked bond formed between the third cysteine residues at the C-termini of two monomeric proteins (arrow). Lefty lacks this residue and therefore remains as a monomeric protein.
Figure 5. TGF-beta signaling pathway. Binding of a TGF-beta family member to the type II and type I receptor leads to phosphorylation of the type I receptor. The activated type I receptor phosphorylates a receptor-regulated SMAD (R-Smad). Following this phosphorylation, the R-Smad dissociates from the receptor and binds to a common Smad (Smad4). This heterodimer then moves into the nucleus where it associates with a DNA-binding partner, such as Fast1 activating transcription.
Figure 6. Mechanisms regulating biologic activity of TGF-beta. During secretion, a small latent, biologically inactive TGF-beta complex is formed by the non-covalent association of LAP and mature TGF-beta. This complex, binds to LTBPs. This association facilitates TGF-beta secretion and promotes its fixation to the ECM by a transglutaminase (TG) dependent mechanism.
Figure 7. Reduced collagen deposition in stroma by lefty visualized in trichrome stained sections. A: The control transformed GP+E86 fibroblasts transduced with LG retroviral particles have extensively laid down collagen fibers (arrows) at the periphery of the tumor and have invaded surrounding muscle tissue. B: The LEIG transduced fibroblasts have no discernible stroma and show no evidence of collagen fibers. Collagen fibers are seen at the tissues surrounding the tumor (arrows). Bar=250 micrometers.