MECHANISMS AND REGULATION OF TRANSMEMBRANE SIGNALING IN THROMBOSIS, INFLAMMATION, AND CANCER
Our research centers around the following questions: How do membrane receptors transmit signals across the cell membrane? How can we modulate the transmission of these signals to combat diseases? We focus on the cell adhesion receptors that are critically involved in thrombosis, inflammation and tumorigenesis. We take a multidisciplinary approach, using a combination of cell biological, biochemical, and biophysical techniques.
Regulation of ectodomain shedding. Ectodomain shedding is a process in which an integral membrane protein is proteolytically cleaved and its extracellular domain released from the cell. It affects many membrane proteins including growth factor precursors, amyloid precursor proteins, cytokines, cell adhesion receptors, and proteoglycans. Excessive shedding activity often leads to diseases such as cancer, arthritis and neurodegenerative diseases. We are interested in elucidating the molecular mechanisms underlying regulation of ectodomain shedding by intracellular events including protein interactions with the cytoplasmic domain of shedding substrates. Our other focus is, based on what we have learned of the regulation mechanisms, to devise ways to inhibit and modulate shedding of membrane protein substrates, particularly those with significant implications in human diseases.
Structure and function of platelet glycoprotein (GP) Ib-IX-V complex. The interaction between the GP Ib-IX-V complex on the platelet surface and von Willebrand factor (vWF) that marks the injury site in the artery is widely considered as the first step for hemostasis. Upon binding to vWF, the GP Ib-IX-V complex transduces into the platelet an activating signal, leading eventually to platelet aggregation and thrombus formation. Malfunction or lack of the GP Ib-IX-V complex in platelets results in severe bleeding disorders. The GP Ib-IX-V complex consists of nine subunits of four kinds: Ib, Ib, IX and V. Our current focus is to delineate the 3-dimensional organization of the complex, that is, how these subunits evolve, interact with one another and assemble into the functional receptor complex. The insights on the overall organization of the Ib-IX-V complex will help us understand how it mediates signals of vWF-binding across the plasma membrane to activate the platelet, and how the binding activity of this complex is regulated by intracellular signals.
Mo X, Nguyen NX, Mu FT, Yang W, Luo SZ, Fan H, Andrews RK, Berndt MC, Li R. Trans-membrane and trans-subunit regulation of ectodomain shedding of platelet glycoprotein Ibα. J Biol Chem 2010 August 17 [Epub ahead of print]
Li R. A hypothesis that explains the heterogeneity of drug-induced immune thrombocytopenia. Blood 115: 914, 2010.
Mo X, Nguyen NX, McEwan PA, Zheng X, López JA, Emsley J, Li R. Binding of platelet glycoprotein Ib through the convex surface of leucine-rich repeats domain of glycoprotein IX. J Thromb Haemost. 2009 Jun 30. [Epub ahead of print]
X. Mo, S.-Z. Luo, J. A. López, R. Li. Juxtamembrane basic residues in glycoprotein Ib cytoplasmic domain are required for assembly and surface expression of glycoprotein Ib-IX complex. FEBS Lett. 582: 3270-3274, 2008.
S.-Z. Luo, R. Li. Specific heteromeric association of four transmembrane peptides derived from platelet glycoprotein Ib-IX complex. J. Mol. Biol. 382: 448-457, 2008.
X. Mo, S.-Z. Luo, A. D. Munday, W. Sun, M. C. Berndt, J. A. López, J.-F. Dong, R. Li. The membrane-proximal inter-subunit disulfide bonds in glycoprotein Ib influence the receptor binding to von Willebrand factor. J. Thromb. Haemost. 6: 1789-1795, 2008.
S.-Z. Luo, X. Mo, J. A. López, R. Li. Role of the transmembrane domain of glycoprotein IX in the assembly of glycoprotein Ib-IX complex. J. Thromb. Haemost. 5: 2494-2502, 2007.
S.-Z. Luo*, X. Mo*, V. Afshar-Kharghan, S. Srinivasan, J. A. López, R. Li. Glycoprotein Ib forms disulfide bonds with two glycoprotein Ib subumits in the resting platelet. Blood 109: 603-9, 2007. (Commentary in Blood 109: 393-4)
X. Mo, N. Lu, A. Padilla, J. A. López, R. Li. The transmembrane domain of glycoprotein Ib is critical to efficient expression of glycoprotein Ib-IX complex in the plasma membrane. J. Biol. Chem. 281: 23050-9, 2006.
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