Biochemistry

Laurie Erb

Research Associate Professor of Biochemistry

E-mail:erbl@missouri.edu

Office: 540F Bond Life Sciences Center

Mail: Christopher S. Bond Life Sciences Center
540F Bond Life Sciences Center
University of Missouri
Columbia, MO 65211

Phone: 573-884-2065

Fax: 573-884-2537

Lab: 573-882-1708

Educational background

Research description

Our general mission is to understand how tissue damage causes the body to mount an inflammatory response. Over the last decade, a new hypothesis of how our bodies respond to tissue damage or pathogenic invasion has taken place. The current prevailing hypothesis is that an inflammatory response does not occur solely in response to foreign or nonself molecules but, rather, in response to self molecules released from damaged tissue. The self molecules responsible for mounting an inflammatory response have not been conclusively identified, although it is speculated that they must have the following features: 1) they should be easily and quickly generated in the extracellular space, probably by release from an existing intracellular pool, 2) under resting conditions their extracellular concentration should be close to zero to allow a high signal-to-noise ratio upon release, 3) they should be highly mobile in the pericellular environment, 4) they should be recognized by specific receptors expressed in immune cells, and 5) they should be easily destroyed once they reach the extracellular space. Since nucleotides meet all these criteria, these molecules and their cell surface receptors (P2 receptors) have emerged as key players in the process of inflammation.

In injured tissue, ATP and other nucleotides are immediately released from damaged cells where they assist in localized platelet aggregation by activating platelet P2Y₁ and P2Y₁₂ receptors. Aggregated platelets then release molar quantities of ATP from secretory vesicles, leading to a variety of P2 receptor-mediated inflammatory events, including blood vessel dilation, cytokine release and leukocyte recruitment from the blood to the site of injury. Other sources of extracellular ATP in damaged tissue include hypoxic red blood cells, activated neurons and migrating leukocytes which release bursts of ATP at their leading edge. Although several subtypes of P2 receptors have been reported to mediate pro-inflammatory responses, the P2Y₂ receptor subtype (P2Y₂R) appears to be unique in its ability to be upregulated in vascular tissue under conditions of stress or injury. By examining P2Y₂R function in immune and vascular cells and in in vivo injury models we hope to provide a better understanding of how nucleotides influence inflammation and wound healing.

The P2Y₂R, which is normally expressed in monocytes and neutrophils, has been shown to control adhesion of leukocytes to vascular endothelium, an early event in the inflammatory process. Recent studies in our lab have begun to delineate the molecular basis of P2Y₂R-mediated monocyte adhesion, chemotaxis and diapedesis or migration of monocytes/leukocytes across the endothelial layer that lines blood vessels. Specifically, we have identified consensus Src-homology-3 (SH3) binding sites in the intracellular C-terminal tail of P2Y₂R that bind directly to Src and allow the P2Y₂R to co-localize with and transactivate several growth factor receptors, including VEGFR-2 in endothelial cells. Furthermore, we have found that transactivation of VEGFR-2 by the P2Y₂R causes upregulation of VCAM-1, a cell adhesion molecule important for monocyte adherence. Other studies in our lab have demonstrated that an integrin-binding domain in the P2Y₂R allows this receptor to associate with α_Vβ₃ and α_Vβ₅ integrins, adhesion molecules that are important for both leukocyte migration and angiogenesis. Since the P2Y₂R co-localizes with growth factor receptors and also with α_Vβ_3/5 integrins, we speculate that the P2Y₂R may be a component of a large signaling complex containing integrins and proteins associated with integrins such as Src, focal adhesion kinase, Pyk2, growth factor receptors, and the actin cytoskeleton. A better understanding of the nature of these multi-protein interactions and signaling events involving P2Y₂Rs will likely identify intervention points for selectively controlling P2Y₂R activities that mediate inflammatory responses, leading to new treatments for inflammatory disorders, such as atherosclerosis and ulcers.

Selected publications

Erb, L., J. Liu, J. Ockerhausen, Q. Kong, R.C. Garrad, K. Griffin, C. Neal, B. Krugh, L.I. Santiago-Perez, F.A. Gonzalez, H.D. Gresham, J.T. Turner, and G.A. Weisman. 2001. An RGD sequence in the P2Y₂ receptor interacts with αVβ3 integrins and is required for Go-mediated signal transduction. J Cell Biol. 153:491-501.

Seye, C.I., Q. Kong, L. Erb, R.C. Garrad, B. Krugh, M. Wang, J.T. Turner, M. Sturek, F.A. Gonzalez, and G.A. Weisman. 2002. Functional P2Y₂ nucleotide receptors mediate uridine 5'-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries. Circulation. 106:2720-6.

Liu, J., Z. Liao, J. Camden, K.D. Griffin, R.C. Garrad, L.I. Santiago-Perez, F.A. Gonzalez, C.I. Seye, G.A. Weisman, and L. Erb. 2004. SH3 binding sites in the P2Y₂ nucleotide receptor interact with Src and regulate activities of Src, Pyk2, and growth factor receptors. J Biol Chem. 279:8212-8.

Seye, C.I., N. Yu, F.A. Gonzalez, L. Erb, and G.A. Weisman. 2004. The P2Y₂ Nucleotide Receptor Mediates Vascular Cell Adhesion Molecule-1 Expression through Interaction with VEGF Receptor-2 (KDR/Flk-1) J. Biol. Chem. 279:35679-86.

Kaczmarek, E., L. Erb, K. Koziak, R. Jarzyna, M.R Wink, O. Guckelberger, J.K. Blusztajn, V. Trinkaus-Randall, G.A. Weisman, S.C. Robson. 2005. Modulation of endothelial cell migration by extracellular nucleotides. Thromb Haemost. 93: 735-42.

Bagchi, S., Z. Liao, F.A. Gonzalez, N.E. Chorna, C.I. Seye, G.A. Weisman, L. Erb. 2005. The P2Y₂ nucleotide receptor interacts with αV integrins to activate Go and induce cell migration. J. Biol. Chem. 280:39050-7.

Erb, L., Z. Liao, C.I. Seye, and G.A. Weisman. 2006. P2 receptors: intracellular signaling. Eur. J. Physiol. 452: 552-62.

Liao, Z., C.I. Seye, G.A. Weisman, and L. Erb. 2007. The P2Y₂ nucleotide receptor requires interaction with α_V integrins to access and activate G12. J. Cell. Sci. 120: 1654-62.

Beldi, G., Y. Wu, X. Sun, M. Imai, K. Enjyoji, E. Csizmadia, D. Candinas, L. Erb, and S.C. Robson. 2008. Regulated catalysis of extracellular nucleotides by vascular CD39/ENTPD1 is required for liver regeneration. Gastroenterology. 135 (5): 1751-1760.