Isaac Rabinovitz Lab
The general goal of our research is to understand the molecular basis of carcinoma invasion, focusing on the regulatory mechanisms of cell adhesion. One of the hallmarks in early carcinoma is the disappearance of the hemidesmosome (HD), a multi-protein structure used by epithelial cells to firmly attach to the basement membrane. These anchoring structures hinder cell movement and need to be disassembled to allow the cell to migrate and invade. Our research seeks to understand how carcinoma cells manage to free themselves of these anchoring structures. One aspect of our studies seeks to unravel signaling pathways in carcinoma cells that promote the disassembly of the hemidesmosome, such as those elicited by growth factors. Another aspect is the structural and functional modifications that HDs undergo upon activation of these signaling pathways. Phosphorylation of the HD components is thought to play an important role in HD disassembly. We and others have shown that phosphorylation of the a6b4 integrin, a laminin receptor and a component of the HD, can regulate the stability of the HD. Growth factors can activate a PKC-dependent signaling pathway that promotes a6b4 phosphorylation and induces HD disassembly. We have successfully identified a cluster of serines in the b4 subunit,
1360 and S
1364 , that are phosphorylated upon growth factor stimulation and mediate HD disassembly. These serines are part of the connecting segment of b4, a region that has been shown to contain several other regulatory elements.
Understanding the dynamics of HDs will eventually allow us to test whether inhibition of hemidesmosome disassembly could prevent invasion. This information will be valuable in the future design of rational approaches to prevent carcinoma dissemination.
Another line of study that we are pursuing is the mechanical and mechano-sensory functions of a6b4 and the hemidesmosome. Our recent studies have shown that a6b4 in colon carcinoma cells is involved in the generation of traction and that this function may be important in basement membrane remodeling, which could allow carcinoma cells to clear paths for invasion.
Selected Recent Publication
Rabinovitz, I., Tsomo, L., and Mercurio A.M., PKC-a phosphorylation of specific serines in the connecting segment of the b4 integrin regulates the dynamics of hemidesmosomes. Molecular and Cellular Biology 10:4351-60, 2004
Rabinovitz, I., and Mercurio AM. Dynamic Functions of the a6b4 Integrin in Carcinoma. In "
Cell motility in Cancer Invasion and Metastasis" Allan Wells, ed. New York, NY: Kluwer Academic Publishers,. 29 pg, 2005 (in press).