Overgrowth Syndromes and the Regulation of Signaling Complexes by Proteoglycans

The genetic studies of mice and flies show that proteoglycans and HS biosynthetic and modifying enzymes affect patterning during development. The activities of these genes are expressed at least in part by their influence on the signaling of two key secreted growth-factor families, the Wnts and the TGF-β/BMPs. However, what precisely are HSPGs doing at the cell surface, and how might they affect signaling there? One model, referred to above, maintains that HSPGs serve as growth-factor coreceptors by helping to deliver ligands to the signaling receptor. However, HSPGs might also affect molecular assemblies at the cell surface by other means, and there is experimental support for two other mechanisms: (1) HS as an allosteric regulator changing the conformation of proteins that bind to specific HS sequences and (2) HSPGs as “molecules of encounter” facilitating the interaction between two other components. As shown in figure 2figure 2, both these mechanisms play a role in the regulation, by HS, of blood coagulation on the luminal surface of endothelial cells (Rosenberg et al. 1997xHeparan sulfate proteoglycans of the cardiovascular system: specific structures emerge but how is synthesis regulated?. Rosenberg, RD, Shworak, NW, Liu, J, Schwartz, JJ, and Zhang, L. J Clin Invest Suppl. 1997; 100: S67–S75See all References1997). The serine protease inhibitor antithrombin (AT) inactivates the proteases thrombin and factor Xa as a means of regulating the coagulation cascade. Heparin—a highly sulfated form of HS—accelerates AT-protease interactions by two different mechanisms. First, heparin binding to AT induces conformational changes that accelerate AT-Xa–complex generation. Second, both AT and thrombin bind to one long-chain heparin molecule, promoting AT-thrombin association. The regulation of proteases by HSPGs might provide a paradigm for understanding how pipe controls dorsal-ventral patterning during Drosophila development.These models provide a basis for the understanding of how loss of GPC3 might cause the overgrowth, patterning defects, and tumor susceptibility that characterize SGBS. It has been suggested that GPC3 binds to insulin-like growth factor–2 (IGF2) and that loss of GPC3 might increase the levels of IGF2, hence promoting tissue growth. However, rat Gpc3 does not bind to IGF2, which casts some doubt on this model (Song et al. 1997xOCI-5/rat glypican-3 binds to fibroblast growth factor-2 but not to insulin-like growth factor-2. Song, HH, Shi, W, and Filmus, J. J Biol Chem. 1997; 272: 7574–7577Crossref | PubMed | Scopus (102)See all References1997), although it is possible that GPC3 affects IGF2 activity indirectly, perhaps by regulating IGF2-binding proteins. It seems very unlikely, however, that all the phenotypes associated with SBGS will be accounted for by defects in IFG2 activity alone. The evidence from Drosophila and from cell-culture systems suggests that many different growth factors are likely to be affected by loss of GPC3. Clearly, Wnt and TGF-β/BMP signaling could be compromised in SGBS patients. TGF-β is a well-known inhibitor of cell-cycle progression, and the loss of GPC3 could compromise TGF-β–mediated control of cell division. Disruptions in TGF-β–signaling components, including the Smads, and in TGF-β receptors are associated with tumor progression (Moskaluk and Kern 1996xCancer gets Mad: DPC4 and other TGF-b pathway genes in human cancer. Moskaluk, CA and Kern, SE. Biochim Biophys Acta. 1996; 1288: M31–M33PubMedSee all References1996), suggesting that the neoplasia associated with SBGS could reflect a loss of normal TGF-β activity.Recently, mouse Gpc3 has been shown to affect apoptosis in different tissue-culture cell lines (Gonzalez et al. 1998xOCI-5/GPC3, a glypican encoded by a gene that is mutated in the Simpson-Golabi-Behmel overgrowth syndrome, induces apoptosis in a cell line-specific manner. Gonzalez, AD, Kaya, M, Shi, W, Song, H, Testa, JR, Penn, LZ, and Filmus, J. J Cell Biol. 1998; 141: 1407–1414Crossref | PubMed | Scopus (148)See all References1998). Perhaps some of the phenotypes of SGBS patients, such as hexadactyly, are the consequence of defects in programmed cell death during development. In this regard, it is interesting to note that TGF-β/BMPs have been implicated in the induction of programmed cell death during limb morphogenesis (Merino et al. 1998xMorphogenesis of digits in the avian limb is controlled by FGFs, TGF betas, and noggin through BMP signaling. Merino, R, Ganan, Y, Macias, D, Economides, AN, Sampath, KT, and Hurle, JM. Dev Biol. 1998; 200: 35–45Crossref | PubMed | Scopus (175)See all References1998). In sum, the many SGBS phenotypes found probably reflect the variety of signaling events that are affected by loss of this cell-surface proteoglycan. The analysis of proteoglycans will yield a great deal of insight into the molecular topography of the cell surface and the orchestration of signaling events that take place there.