Immunology Graduate Program | University of California, San Francisco

Steven Rosen, PhD

Roles of biological sulfation in leukocyte trafficking and tumorigenesis

Professor, Departments of Anatomy
Investigator, Cardiovascular Research Institute
Member, UCSF Comprehensive Cancer Center
513 Parnassus HSW 1322, Box 0452
San Francisco, CA. 94143

Phone: 476-1579 tel
steven.rosen@ucsf.edu

Description of Research

Research Interests: 1) Role of selectins and their sulfated ligands in leukocyte trafficking during lymphocyte homing and inflammatory recruitment; 2) role of extracellular heparan sulfate degrading sulfatases in tumorigenesis.

We currently are pursuing two main areas of research: 1) molecular mechanisms of leukocyte-endothelial adhesion; and 2) the role of heparan sulfate-degrading sulfatases in cancer. The first project focuses on the role of L-selectin, a lectin-type receptor on leukocytes that mediates leukocyte adhesion to activated endothelium. This receptor recognizes endothelial ligands which contain key sulfated carbohydrate determinants. We are interested in the sulfotransferases that synthesize these ligands and how these enzymes are regulated within activated endothelium at inflammatory sites. Toward this end, we are studying mice that are null for two sulfotransferases that are expressed in high endothelial venules of lymphoid organs. These mice exhibit marked deficiency in lymphocyte homing to lymph nodes. We are studying the role of the L-selectin/endothelial ligand adhesion system in the recruitment of lymphocytes and other leukocytes to sites of chronic inflammation, in particular joints in rheumatoid arthritis and inflamed airways in asthma. We are further interested in the signaling responses that are induced in leukocytes when L-selectin is ligated through interaction with specific ligands.

The second main direction of the laboratory concerns two novel sulfatases, called Sulf-1 and Sulf-2 which we cloned a few years ago. These enzymes are targeted to the cell surface and act extracellularly. They remove specific internal sulfate residues (i.e., glucosamine-6-sulfate) from heparan sulfate proteoglycans (HSPGs) on the cell surface and in the extracellular matrix. This desulfation step regulates the ability of heparan sulfate chains to bind specific protein ligands and therefore exerts control on the bioavailability of the ligands. Marked upregulation of Sulf expression is seen in several cancers, notably breast, pancreatic, and lung cancers. We are investigating the possible causal role of the Sulfs in regulating cell proliferation and angiogenesis during tumor growth through their ability to modulate the interaction of growth factors and angiogenic factors with HSPGs. The Wnt signaling pathway is promoted by the action of the Sulfs. In a number of cancers, this developmental signaling pathway is reactivated where it promotes cell proliferation and antagonizes apoptosis. We are therefore investigating the role of the Sulfs in several examples of Wnt-signaling dependent cancers: pancreatic, breast, and lung.

Pablos, J.L., B. Santiago, D. Tsay, M.S. Singer, G. Palao, M. Galindo, and S.D. Rosen. (2005). A HEV-restricted sulfotransferase is expressed in rheumatoid arthritis synovium and is induced by lymphotoxin-alpha/beta and TNF-alpha in cultured endothelial cells. BMC Immunol. 6

Uchimura, K., Gauguet, J.-M., Singer, M.S., Tsay, D., Kannagi, R., Muramatsu, T., von Andrian, U.H., and Rosen, S.D. (2005). A major class of L-selectin ligands is eliminated into mice deficient in two HEV-expressed sulfotransferases. Nat Immunol 6:1105-13.

Uchimura, K., Morimoto-Tomita, M., and Rosen, S.D. (2006). Measuring the activities of the Sulfs, two novel heparin/heparan sulfate endosulfatases. Meth. Enzymol. 416: 243-253

Morimoto-Tomita, M., Uchimura, K., Bistrup, A., Lum, D.H., Egeblad, M., Werb, Z., and Rosen, S.D. (2005). Sulf-2, a pro-angiogenic heparan sulfate endosulfatase, is upregulated in breast cancer. Neoplasia 7: 1001-1010

Uchimura, K., Morimoto-Tomita, M., Bistrup, A., Li, J., Lyon, M., Gallagher, J., Werb, Z., and Rosen, S.D. (2006). HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1. BMC Biochemistry 7:2.

Rosen, S.D. (2006). Homing in on L-selectin. J. Immunol 177: 3-4.

Yang, J., S. D. Rosen, P. Bendele, and S. Hemmerich. (2006). Induction of PNAd and N-acetylglucosamine 6-O-sulfotransferases 1 and 2 in mouse collagen-induced arthritis. BMC Immunol 7:12.

Uchimura, K. and Rosen, S. D. (2006). Sulfated L-Selectin ligands as a therapeutic target in chronic inflammation. Trends in Immunology, 27:559-565.

Lum, D.H., J.H. Tan, S.D. Rosen, and Z. Werb. (2007). Gene trap disruption of the mouse heparan sulfate 6-O endosulfatase, Sulf2. Mol Cell Biol 27: 678-688..

Veerman, K. M., Williams, M. J., Uchimura, K., Singer, M. S., Merzaban, J. S., Naus, S., Carlow, D. A., Owen, P., Rivera-Nieves, J., Rosen, S. D., and Ziltener, H. J (2007). PSGL-1 interaction with CCL21/CCL19 facilitates efficient T cell homing to secondary lymphoid organs. Nat Immunol 8: 532-9

Nawroth, R., A. van Zante, S. Cervantes, M. McManus, M. Hebrok, and S.D. Rosen. 2007. Extracellular sulfatases, elements of the Wnt signaling pathway, regulate growth and tumorigenicity of human pancreatic cancer cell lines. PLoS ONE 2:e392

Kanda, H., R. Newton, R. Klein, Y. Morita, M. D. Gunn, and S. D. Rosen. 2008. Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat Immunol 9:415-423.

Kerr, S.C., C. Fieger, K. Snapp, and S.D. Rosen. 2008. Endoglycan, a member of the CD34 family of sialomucins, is a ligand for the vascular selectins, J. Immunol. 181: 1480-90.