Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/30717
Title: INVESTIGATIONS OF THE NEW CELL ADHESION MOLECULE HEPACAM: ITS CONNECTION WITH THE INTEGRIN-DEPENDENT SIGNALING AND ITS PROTEOLYTIC CLEAVAGE
Authors: ZHANG TING
Keywords: hepaCAM, cell adhesion molecule, integrin, cell adhesion, cell migration, proteolytic cleavage
Issue Date: 6-Apr-2011
Source: ZHANG TING (2011-04-06). INVESTIGATIONS OF THE NEW CELL ADHESION MOLECULE HEPACAM: ITS CONNECTION WITH THE INTEGRIN-DEPENDENT SIGNALING AND ITS PROTEOLYTIC CLEAVAGE. ScholarBank@NUS Repository.
Abstract: Cell adhesion is a fundamental feature of multi-cellular organisms. Cell-cell and cell-extracellular matrix (ECM) adhesions are mediated by cell adhesion molecules (CAMs) which are classified into five major families: immunoglobulin (Ig)-like CAMs, integrins, selectins, cadherins and heparin sulfate proteoglycans (HSPG). Previously, our group identified a novel gene hepaCAM. Mapped to human chromosome 11q24, hepaCAM encodes a CAM of the Ig-like superfamily. The gene is widely expressed in normal human tissues and frequently silenced in a variety of tumors. Re-expression of hepaCAM in cancer cell lines significantly inhibits cell growth. The frequent loss of hepaCAM in human cancers and its inhibitory effect on cell growth fulfill two of the most important criteria to define tumor suppressors. The present study aims to further investigate the characteristics of hepaCAM, mainly focusing on two subjects: 1) the connection between hepaCAM and the integrin-dependent signaling, and 2) the proteolytic cleavage of hepaCAM. The first study demonstrates that when re-expressed in MCF7 cells, hepaCAM accelerates the initial cell attachment and cell spreading. Both the velocity and directionality of cell migration are also enhanced. In addition, hepaCAM is found to be physically associated with integrin ß1; moreover, hepaCAM up-regulates the protein expression of integrin ß1 as well as its active form. Interestingly, hepaCAM regulates the assembly of the focal contacts and alters the activity of Rho family GTPases time dependently. The altered signaling mediated by hepaCAM results in an altered organization of the actin cytoskeleton, supporting a migratory phenotype. In the second study, a proteolytic cleavage of hepaCAM is identified. This cleavage generates a 25-kD product containing mainly the cytoplasmic domain of hepaCAM. The cleavage is promoted by the Ca2+ ionophore ionomycin. The involvement of proteasome, calpain-1 and cathepsin B are also indicated. Furthermore, the cytoplasmic truncated mutant of hepaCAM fails to promote cell-ECM adhesion and migration, and loses the inhibitory effect on cell growth, suggesting a regulatory role of the cleavage in hepaCAM functions. In conclusion, the first study uncovers a novel connection between hepaCAM and the integrin-dependent signaling, providing the molecular basis for the hepaCAM-mediated cell-ECM adhesion and migration. The second study explores the mechanisms that are involved in hepaCAM cleavage and sheds light on the possibility of hepaCAM cleavage functioning as a regulatory switch.
URI: http://scholarbank.nus.edu.sg/handle/10635/30717
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