The research in my laboratory focuses on a specific family of cell surface receptors, the syndecans, and their role in initiating intracellular signal transduction. The syndecans are a four member family of cell surface heparan sulfate proteoglycans that mediate adhesion to the extracellular matrix. The heparan sulfate chains also bind to growth factors, such as the fibroblast growth factors, and regulate their signaling. The consequences of these activities, and their defects, are important to our understanding of cancer. Metastatic cells show defects in cell adhesion that correlate with altered syndecan expression. And, growth factors such as the FGFs are potent tumor proliferation and survival factors; their importance in tumor survival is traced to their control of angiogenesis necessary for tumor growth. A current question in syndecan biology is how these receptors form signaling complexes at the cell surface. With regard to FGF signaling, it is now clear that the heparan sulfate chains form part of a tenary complex at the cell surface that includes the heparan sulfate chain itself, the FGF and the FGF receptor tyrosine kinase; each of these components has binding sites for the two others. Secondly, however, the heparan sulfate chain serves to oligomerize the activated receptors into a higher affinity complex which is the main signaling component at the cell surface; the receptors brought into close proximity to one another carry out transphosphorylation amongst the cytoplasmic domains which activates downstream signaling pathways. Numerous questions remain to be answered regarding the regulatory role of heparan sulfate in this signaling complex. As the sulfation sequence in heparan sulfates can be quite variable, their ability to bind specific FGFs and FGF receptors is equally variable. This, in turn, determines whether or not a given proteoglycan type will participate in the formation of a signaling complex. Ongoing studies that localize specific heparan sulfates in vivo show that they differ in their ability to form signaling complexes with specific FGFs. Secondly, the role of the syndecan protein itself as part of the intracellular signaling complex remains to be explored. Once answers to these questions are known, it may be possible to construct mimetics of the stimulatory or inhibitory heparan sulfates that may directly control growth factor signaling in vivo during tumor growth. A second focus is the molecular interactions of the syndecan core proteins. As we have done with the heparan sulfate chains, we are attempting to identify discrete domains within the core proteins that have regulatory activity. Current evidence demonstrates that at least three distinct regions of the syndecan cytoplasmic domain interact with intracellular cytoskeletal and signaling molecules; these interactions may be regulated by the phosphorylation of tyrosines or serines within these domains. In addition, the transmembrane and extracellular protein domains have important molecular interactions. These serve to incorporate each of the syndecan family members into specific cell surface adhesion complexes that are anchored to the cytoskeleton and to a signaling scaffold within the cytoplasm. Thus, syndecan expression at cell surfaces is an important regulatory mechanism for cell-cell and cell-matrix adhesion.
Alan C. Rapraeger, PhD
1111 Highland Ave
Madison, WI 53705
PhD, University of California, Berkeley
Cell surface proteoglycans, heparin-binding growth factors
Haiyao Wang, LuAnn Leavitt, Ravishankar Ramaswamy, Alan C Rapraeger. Interaction of syndecan and alpha6beta4 integrin cytoplasmic domains: regulation of ErbB2-mediated integrin activation. J. Biol. Chem.: 2010, 285(18);13569-79
DeannaLee M Beauvais, Alan C Rapraeger. Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation. J. Cell. Sci.: 2010, 123(Pt 21);3796-807
Beauvais DM, Ell BJ, McWhorter AR, Rapraeger AC. Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor. J Exp Med. 2009 Mar 16;206(3):691-705. Epub 2009 Mar 2.
Beauvais, D.M., Ell, B.J., McWhorter, A. R. and Rapraeger, A.C. (2009). Syndecan-1 regulates αv β3 and αv β5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor. J. Exp. Med., 206: 691-705. (See commentary: Maxmen, A. (2009). A syndecan-based tumor stopper. JEM 206:493). Ji, Y., and Rapraeger, A.C. (pending). Induction of E-cadherin and Cell Adhesion in Mammary Carcinoma Cells by Syndecan-1. J. Cell Sci., under review.
Wang, H., Leavitt, L., Ramaswamy, R. and Rapraeger, A.C. (pending). Activation of alpha6beta4 integrin signaling is regulated by syndecan cytoplasmic domain. J. Biol. Chem., submitted.
Kyle J McQuade, DeannaLee M Beauvais, Brandon J Burbach, Alan C Rapraeger. Syndecan-1 regulates alphavbeta5 integrin activity in B82L fibroblasts. J. Cell. Sci.: 2006, 119(Pt 12);2445-56