Outside-In-and-Back-Outside Signals

Abstract

Monocytes participate in inflammatory responses in the immune system, wound repair, and other processes. They interact with activated platelets and endothelial cells through a protein in the monocyte cell membrane called P-selectin glycoprotein-1 (PSGL-1). But emerging evidence indicates that this is just one step in a complex network of interactions that regulate monocyte adhesion and migration. Mahoney et al. show that binding of PSGL-1 to P-selectin causes increased activity of mTOR (mammalian target of rapamycin; a protein kinase implicated in control of cell growth and proliferation) and consequent enhanced translation of messenger RNA encoding the urokinase plasminogen activator receptor (UPAR). As the name betrays, UPAR binds and thus localizes the protease UPA, which influences adhesion and migration through its protease activity and through activation of UPAR signaling. UPAR is also regulated at the level of transcription, and has multiple actions, including formation of regulatory complexes with integrins and interaction with the matrix molecule vitronectin. Indeed, the increased synthesis of UPAR identified by Mahoney et al. in response to PSGL-1 caused enhanced adhesion of monocytes to vitronectin. Thus, an "outside-in" signal from interaction of a cell with P-selectin triggers an intracellular signaling pathway that ultimately signals back to the outside through increased expression of UPAR, which then enhances binding to vitronectin. The authors note that such changes in interactions at the cell surface could mediate some of the therapeutic effects of rapamycin. T. S. Mahoney, A. S. Weyrich, D. A. Dixon, T. McIntyre, S. M. Prescott, G. A. Zimmerman, Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes. Proc. Natl. Acad. Sci. U.S.A. 98 , 10284-10289 (2001). [Abstract] [Full Text]