[Frontiers in Bioscience 7, d793-807, April 1, 2002]

ROLES OF TGF-BETA IN HEPATIC FIBROSIS

A. M. Gressner, R. Weiskirchen, K. Breitkopf, S. Dooley

Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, D-52074 Aachen, Germany

FIGURES

Figure 1. Schematic presentation of the extracellular processing of latent transforming growth factor-beta, (modified after (155)). TGase: Tissue transglutaminase; TSP: Thrombospondin.

Figure 2. Solution structure of recombinant transforming growth factor-beta 1. (A) Spacefill model of human recombinant TGF-beta 1 derived from the solution structure of TGF-b 1 solved by nuclear magnetic resonance (NMR) spectroscopy. (B) Overlay of 17 independent structures of recombinant human TGF-beta 1 as determined by heteronuclear NMR showing the mirror image like structure of the homodimer. All backbone heavy atoms (N, Ca , and C') are shown. The models (A, B) were generated using the coordinates deposited in the Brookhaven Protein Databank (PDB) under the accession number 1KLA and the RasWin Molecular Graphics Software (Windows Version 2.7.1.1). The structural characteristics of TGF-beta 1 in solution generally agree closely with the derived crystal structures of TGF-beta 2. For details see (156-160).

Figure 3. Simplified scheme of the transforming growth factor-b/Smad pathway. Following ligand binding, the TGF-beta type II receptor kinases phosphorylate cytoplasmic domains and thereby activate transforming growth factor type I receptor (TbR-I). The Smads then act as TbR-I activated signaling effectors, which, following receptor induced phosphorylation and interaction with Smad4, translocate into the nucleus and activate transcription of selected target genes. Specific mechanisms at nearly all levels have been identified that activate or repress TGF-beta signaling. The adaptor protein Smad anchor for receptor activation (SARA), antagonistic Smad7, several transcription activators and repressors and cofactors, which cooperate with activated Smad complexes are indicated (for reviews see (44-46)).

Figure 4. Determinants of the steady state level of plasma transforming growth factor-beta. Possible sources and clearance organs are indicated. Nearly the total plasma TGF-beta is present in a latent (inactive) form and integrated into a large complex containing a2-macroglobulin. Endoglin binds TGF-beta to the surface of vascular endothelial cells.