Tgfp Superfamily And Signal Transduction
The TGF-P family encodes several secreted factors that regulate a wide variety of cellular processes. The members include TGF-P 1-3, activins, inhibins, BMPs, and growth and differentiation factors (GDFs) (16,17). These secreted proteins bind to type-I and type-II receptors expressed on the cell surface (Fig. 1). There are seven type I, also termed activin receptor-like kinases (Alk), and five type-II receptors, with specific ligand-binding specificity (16). The receptors contain intracellular serine-threonine kinase domains. On binding of ligand, the constitutively active type-II receptor activates the type-I receptor by phosphorylation. This activated receptor then phosphorylates downstream signaling effectors, called Smad proteins (Fig. 1). BMP-mediated signaling activates receptor Smads 1, 5, and 8, whereas activin and TGF-P activate Smads 2 and 3. These activated Smads interact with the common Smad 4, and this complex translocates to the nucleus to regulate target gene transcription. Two inhibitory Smad proteins, Smads 6 and 7, negatively regulate BMP and TGF-P-mediated signaling, respectively. Smad-mediated signaling can be terminated by ubiquitin-mediated degradation. Smurf 1 targets Smads 1 and 5 for destruction (18), Smurf 2 targets Smad 2 (19), and the SCF/Roc1 complex mediates degradation of Smad 3 (20). Moreover, interaction of these ubiquitin-regulatory factors with inhibitory Smads is involved in degradation of the type-I receptor. Interaction of Smurf 1 with Smad 7 targets the TGF-P type-I receptor for degradation (21) and Smurf 1 and Smad 6 target the BMP type-I receptor for degradation (22).
The steps leading to receptor activation are regulated at multiple levels. Outside of the cell, the access of TGF-P superfamily ligands to their receptors is controlled by proteins that function to sequester ligands from their respective receptors. Processing of the TGF-P proprotein in the Golgi results in the formation of a latent complex (23,24). The latency-associated protein LAP1, which is the cleaved amino terminus of the TGF-P proprotein, together with latent TGF-P-binding protein 1 and the active TGF-P homodimer, constitute the large latent complex, which associates with the extracellular matrix and can be released and activated by proteolytic cleavage.
Fig. 1. Schematic BMP and TGF-P signaling (see text for details). Ligands bind to type-I and type-II transmembrane receptors. Access of ligands is enhanced or suppressed by extracellular interacting proteins. Type-I receptors phosphorylated by type-II receptors phosphorylate regulatory Smad proteins at serine residues to promote interactions with the ubiquitous co-Smad 4 or with inhibitory Smads 6 and 7. The activated Smad-co-Smad complex translocates to the nucleus to regulate gene expression. Unique ubiquitin ligases, Smurfs, regulate Smad degradation. PAI-1, plasminogen activator inhibitor-1; ILK, integrin-linked kinase stimulated in the medullary collecting duct by BMP-7 (71).
Fig. 1. Schematic BMP and TGF-P signaling (see text for details). Ligands bind to type-I and type-II transmembrane receptors. Access of ligands is enhanced or suppressed by extracellular interacting proteins. Type-I receptors phosphorylated by type-II receptors phosphorylate regulatory Smad proteins at serine residues to promote interactions with the ubiquitous co-Smad 4 or with inhibitory Smads 6 and 7. The activated Smad-co-Smad complex translocates to the nucleus to regulate gene expression. Unique ubiquitin ligases, Smurfs, regulate Smad degradation. PAI-1, plasminogen activator inhibitor-1; ILK, integrin-linked kinase stimulated in the medullary collecting duct by BMP-7 (71).
Extracellular inhibitors of BMP signaling include vertebrate chordin, which binds directly to BMPs through the cysteine-rich (CR) domains containing CXXCXC and CCXXC motifs (25), and CR transmembrane (CRIM1), which can regulate secretion and receptor binding of BMPs (26). Signaling by the activin family of ligands is inhibited by follistatins. BMPs can also be bound by Noggin, DAN/Cerebrus, Gremlin, and Ectodin to suppress signaling (27-29). Resolution of the crystal structure of the BMP-7/Noggin complex reveals that Noggin inhibits BMP-7 by blocking surfaces that are required to interact with both type-I and type-II BMP receptors (30). Whereas chordin blocks BMP/receptor interactions, the CR domain protein KCP/CRIM2 enhances BMP/receptor interactions to increase the efficacy of signaling (31). Similarly, the CR domain protein CTGF enhances TGF-P-mediated signaling, whereas suppressing the BMP-dependent pathway (32). Endoglin, a type-III TGF-P receptor, associates with TGF-P and the type-I and type-II receptor complex increasing TGF-P signaling. Interestingly, BMP-2, but not BMP-7, also binds with endoglin and enhances TGF-P signaling (33).
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