Alan C. Rapraeger, PhD

Portrait of Alan C. Rapraeger, PhD
Professor
Human Oncology
Address: 
3053 WIMR
1111 Highland Ave
Madison, WI 53705
Telephone: 
(608) 262-7577
Focus Groups: 
Cancer Biology
Signal Transduction
Education: 
PhD, University of California, Berkeley
Research Summary: 
Cell surface proteoglycans, heparin-binding growth factors
Research Detail: 

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.

Selected Publications: 
The Hidden Conundrum of Phosphoinositide Signaling in Cancer.Thapa N, Tan X, Choi S, LambertPF, Rapraeger AC, Anderson RA.Trends Cancer. 2016 Jul;2(7):378-390. Epub 2016 Jun 20. Review.PMID: 27819060
Heparanaseregulation of cancer, autophagy and inflammation: new mechanisms and targets for therapy.Sanderson RD, Elkin M, Rapraeger AC, Ilan N, Vlodavsky I.FEBS J. 2017 Jan;284(1):42-55. doi: 10.1111/febs.13932. Epub 2016 Nov 16. Review.PMID: 27758044
Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth.Beauvais DM, Jung O, YangY, Sanderson RD, Rapraeger AC.Cancer Res. 2016 Sep 1;76(17):4981-93. doi: 10.1158/0008-5472.CAN-16-0232. Epub 2016 Jun 30.PMID: 27364558
Stress-Induced EGFR Trafficking: Mechanisms, Functions, and Therapeutic Implications.Tan X, Lambert PF, Rapraeger AC, Anderson RA.Trends Cell Biol. 2016 May;26(5):352-366. doi: 10.1016/j.tcb.2015.12.006. Epub 2016 Jan 27. Review.PMID: 26827089
Syndecan-1 and Syndecan-4 Capture Epidermal Growth Factor Receptor Family Members and the α3β1 Integrin Via Binding Sites in Their Ectodomains: NOVEL SYNSTATINS PREVENT KINASE CAPTURE AND INHIBIT α6β4-INTEGRIN-DEPENDENT EPITHELIAL CELL MOTILITY.Wang H, Jin H, Rapraeger AC.J Biol Chem. 2015 Oct 23;290(43):26103-13. doi: 10.1074/jbc.M115.679084. Epub 2015 Sep 8.PMID: 26350464
Cytoplasmic domain interactions of syndecan-1 and syndecan-4 with α6β4 integrin mediate human epidermal growth factor receptor (HER1 and HER2)-dependent motility and survival.Wang H, Jin H, Beauvais DM, Rapraeger AC.J Biol Chem. 2014 Oct 31;289(44):30318-32. doi: 10.1074/jbc.M114.586438. Epub 2014 Sep 8.PMID: 25202019
Synstatin: a selective inhibitor of the syndecan-1-coupled IGF1R-αvβ3 integrin complex in tumorigenesis and angiogenesis.Rapraeger AC.FEBS J. 2013 May;280(10):2207-15. doi: 10.1111/febs.12160. Epub 2013 Feb 24. Review.PMID: 23375101
Vascular endothelial-cadherin stimulates syndecan-1-coupled insulin-like growth factor-1 receptor and cross-talk between αVβ3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis.Rapraeger AC, Ell BJ, Roy M, LiX, Morrison OR, Thomas GM, Beauvais DM.FEBS J. 2013 May;280(10):2194-206. doi: 10.1111/febs.12134. Epub 2013 Feb 11.PMID: 23331867
Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation.Beauvais DM, Rapraeger AC.J Cell Sci. 2010 Nov 1;123(Pt 21):3796-807. doi: 10.1242/jcs.067645.PMID: 20971705
Interaction of syndecan and alpha6beta4 integrin cytoplasmic domains: regulation of ErbB2-mediated integrin activation.Wang H, Leavitt L, Ramaswamy R, Rapraeger AC.J Biol Chem. 2010 Apr 30;285(18):13569-79. doi: 10.1074/jbc.M110.102137. Epub 2010 Feb 24.PMID: 20181947