Steven Rosen, PhD, Professor
steven.rosen@ucsf.edu
Administrative Assistant: 415-502-5659

Molecular Mechanisms Of Leukocyte-Endothelial Interactions

We are investigating molecular mechanisms underlying the adhesion of blood-borne lymphocytes to the specialized endothelial cells of lymph node high endothelial venules (HEV). Our early studies suggested that a surface glycoprotein (gp90MEL) on mouse lymphocyte, functioning as a calcium-dependent lectin, mediates this interaction. In collaboration with Genentech, we cloned gp90MEL (now known as L-selectin) and demonstrated the existence of an amino terminal calcium-type lectin domain. Two other cell adhesion proteins cloned at the same time (E-selectin and P-selectin) also possess calcium-type lectin domains. These three proteins, now termed selectins, define a new family of cell adhesion proteins which all function as cell surface lectins in a wide variety of leukocyte-endothelial interactions.

Our recent studies have focused on the identification of the HEV ligands for L-selectin. Using a soluble recombinant form of L-selectin as an affinity probe, we have identified two ligands as GlyCAM-1 and CD34. Both are sulfated, fucosylated, and sialylated mucin-like glycoproteins. A third independent ligand is currently being studied with the goal of molecular cloning.

A major interest of the laboratory is to determine the detailed carbohydrate structure of these ligands. We have shown that both require sialic acid, sulfation and probably fucoyslation for their ligand activity. Actual structuring of GlyCAM-1 has revealed novel O-linked chains that include all of these modifications. We are pursuing the molecular identification of the glycosyltransferases and sulfotransferases that are responsible for the critical modifications of the ligands that allow recognition by L-selectin. Regulation of these modifying enzymes may be of central importance in the establishment of inflammatory sites.

As described above, L-selectin functions normally as a lymphocyte homing receptor. However, this protein also appears to participate in the recruitment of lymphocytes to sites of chronic inflammation. We are studying the nature of the endothelial ligands for L-selectin at these sites and the signals that control their expression.

Complete list of Publications/PubMed

Selected Publications

Tangemann, K., Bistrup, A., Hemmerich, S., and Rosen, S. D. Sulfation of an HEV-expressed ligand for L-selectin: effects on tethering and rolling of lymphocytes. J. Exp. Med 190, 935-941. (1999)

Rosen, S. D. Endothelial ligands for L-selectin: from lymphocyte recirculation to allograft rejection. Am. J. Pathol. 155, 1013-1020. (1999)

Sassetti, C., Van Zante, M., and Rosen, S. D.. Identification of endoglycan, a member of the CD34/podocalyxin family of sialomucins. J. Biol. Chem. 275: 9001-9010. (2000)

Palmeri, D., Van Zante, M., Hemmerich, S., and Rosen, S. D. VE-JAM, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells. J. Biol. Chem. 275: 19139 (2000)

Hemmerich, S. and Rosen, S.D. Carbohydrate sulfotransferases in lymphocyte homing Glycobiology, 10: 849-56. (2000)

Strausbaugh, H. J., and Rosen, S. D. A potential role for annexin 1 as a physiologic mediator of glucocorticoid-induced L-selectin shedding, J.Immunol.166, 6294-6300. (2001)

Hemmerich, S., Bistrup, A., Singer, M. S., Zante, A. v., Lee, J. K., Peters, M., Carminati, J. L., Brennan, T. J., Carver-Moore, K., Leviten, M., Ruddle, N. L., Rosen, S. D. Sulfation of L-selectin ligands by an HEV-Restricted Sulfotransferase Regulates Lymphocyte Homing to Lymph Nodes, Immunity 15: 237-247.(2001)