Timothy Alan Springer, Ph.D

Department	Department of Biological Chemistry and Molecular Pharmacology
Academic Title	Latham Family Professor of Pathology, Harvard Medical School
Phone	617-713-8200
Fax	617-713-8232
Email	Timothy Springer
Location	Harvard Medical School Immune Disease Institute 3 Blackfan Circle, CLSB, Rm 3103

Research Overview

Adhesion molecules on lymphocytes and leukocytes regulate cell interactions in development, antigen recognition, homing, and inflammation. The Springer lab focuses on integrins, Ig superfamily cell adhesion molecules (CAMs), and selectins. Their work is leading to clinical treatments for autoimmune and vascular diseases.

Integrins are the most sophisticated adhesion molecules known. Like many surface molecules, integrins can transmit signals into cells. However, integrins also transmit "inside-out signals." Other receptors transmit signals that impinge on the cytoplasmic and transmembrane domains of integrins. In less than a second, these signals are transmitted to integrin extracellular domains, which undergo conformational movements that enable ligand binding. Thus, integrins can rapidly stabilize contacts between lymphocytes and antigen-presenting cells, and between leukocytes in the bloodstream and endothelium at sites of inflammation. Integrins also mediate cell migration within the body, which involves highly regulated interactions with the actin cytoskeleton and extracellular ligands.

Springer and colleagues are developing a three-dimensional picture of integrins and their ligands, to understand how they bind to one another, the moving parts of the integrin machines and how they are linked together, and the connections to other signaling molecules. The lab also focuses on selectins and a4 integrins that have a unique function in the vasculature. Their receptor-ligand interactions mediate rolling of leukocytes on endothelium, an adhesive modality that enables surveillance for signs of inflammation. They are characterizing the molecular and cellular properties that enable such a transient form of adhesion under the high forces experienced by cells in blood vessels.

Whenever possible, the lab makes connections between basic research and disease. These include inherited defects of integrins in leukocyte adhesion deficiency, ICAM-1 as the cellular receptor for rhinovirus, and SDF-1 as the natural ligand for the HIV coreceptor CXCR4.
 

About Timothy Springer

Dr. Springer graduated from the University of California, Berkeley, and earned a Ph.D. in molecular biology and biochemistry from Harvard University. He is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. In 2004, he was co-recipient of the prestigious Crafoord Prize given by the Royal Swedish Academy of Sciences

Key Publications

• Doud, M.B., Koksal, A.C., Mi, L-Z., Song, G. Lu, C., Springer, T.A. An unexpected fold in the circumsporozoite protein target of malaria vaccines. Proc Natl Acad Sci U S A (2012), Volume: epub ahead of print, Issue: April 30.

• Springer, T.A. and Dustin, M.L. Integrin Inside-Out Signaling and the Immunological Synapse. Curr Opin Cell Biol (2012), Volume: 24, Issue: 1, Pages: 107-115.

• Shi, M., Zhu, J., Wang, R., Chen, X., Mi, L., Walz, T., Springer, T.A. Latent TGF-β structure and activation. Nature (2011), Volume: 474, Issue: 7351, Pages: 343-349.

• Zhang, X., Halvorsen, K, Zhang, C.Z., Wong, W.P., Springer, T. A. Mechanoenzymatic cleavage of the ultralarge vascular protein, von Willebrand Factor. Science (2009), Volume: 324, Pages: 1330-1334.

• Springer, T. A. Structural basis for selectin mechanochemistry Proc. Natl. Acad. Sci. U.S.A. (2009), Volume: 106, Pages: 91-96.

• Zhu, J., Luo, B. H.,Barth, P., Schonbrun, J., Baker, D., Springer, T. A. The structure of a receptor with two associating transmembrane domains on the cell surface: integrin αIIbβ3. Mol. Cell (2009), Issue: 34, Pages: 234-249.

• Zhu, J.; Luo, B. H.; Xiao, T.; Zhang, C.; Nishida, N.; Springer, T. A. Structure of a Complete Integrin Ectodomain in a Physiologic Resting State and Activation and Deactivation by Applied Forces. Mol Cell (2008), Volume: 32, Issue: 6, Pages: 849-861.

• Luo, B-H.; Carman, C. V.; Springer, T. A. Structural basis of integrin regulation and signaling. (2007), Volume: 25, Pages: 619-647