Structure and Function of Cell Adhesion Receptors;
Mechanism of Transmembrane Signaling

My lab is interested in the structural basis of transmembrane signaling of cell adhesion receptors.  We focus on the receptors that are critically involved in hemostasis, inflammation and tumor metastasis.  Our approach is multidisciplinary, using a combination of cell biological, biochemical, and biophysical techniques to study the target receptors and their interacting partners.

Integrin signaling mechanisms. Integrins, a family of heterodimeric surface receptors, are the major structural and communicational link between the cell and the extracellular matrix.  They are actively involved in many important biological processes including cell adhesion, apoptosis, wound healing and immune response.  Despite the importance of these receptors, it is still not clear how the extracellular matrix binds to the integrin and influence cell movement and development.  Current studies aim to illustrate the molecular and structural basis of interactions between integrin and other proteins including co-receptors and intracellular signaling molecules.

Structure and function of platelet glycoprotein Ib-IX-V complex. The interaction between the 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 Ib-IX-V complex transduces into the platelet an activating signal that in consequence converts integrin aIIbb3, another adhesion receptor on the platelet surface, from inactive state to active state, leading eventually to platelet aggregation and thrombus formation.  Malfunction or lack of the Ib-IX-V complex in platelets results in severe bleeding disorders.  The Ib-IX-V complex consists of seven subunits of four kinds: Iba, Ibb, IX and V.  Our current focus is to delineate the 3-dimensional organization of the complex, that is, how these subunits 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 its interaction with vWF and other extracellular and intracellular binding partners, and understand how this complex mediates signals across the plasma membrane to activate the platelet.

Regulatory mechanism 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, and proteoglycans.  Excessive shedding activity often leads to diseases such as cancer, arthritis and neurodegenerative diseases.  For several adhesion receptors, the conformation of their cytoplasmic domain or its association with intracellular proteins can affect their shedding activity on the other side of the membrane.  Our focus is to elucidate the structural mechanism underlying such regulation, and our study may lead to novel therapeutics to control ectodomain shedding.