Two Different PDGF β-Receptor Cohorts in Human Pericytes Mediate Distinct Biological Endpoints

How activation of a specific growth factor receptor selectively results in either cell proliferation or cytoskeletal reorganization is of central importance to the field of pathophysiology. In this study, we report on a novel mechanism that explains how this process is accomplished. Our current investigation demonstrates that soluble platelet derived growth factor(PDGF)-beta activates a cohort of PDGF-beta receptors primarily confined to the lipid raft component of the cell membrane, specifically caveolae. in contrast, cell-bound PDGF-BB delivered via cell-cell contact results in activation and the subsequent up-regulation of a cohort of PDGFB-receptors primarily confined to the non-lipid raft component of the cell membrane. individual activation of these two receptor cohorts results in distinct biological endpoints, cytoskeletal reorganization or cell proliferation. Mechanistically, our evidence suggests that PDGF-BB-bearing cells preferentially stimulate the non-lipid raft receptor cohort through interleukin 1 beta-mediated inhibition of the lipid raft cohort of receptors, leaving the non-raft receptor cohort operational and preferentially stimulated. In human skin injected with PDGF-BB and in tissue reparative processes PDGF beta-receptors colocalize with the caveolae/lipid raft marker caveolin-1. In contrast, in human skin injected with PDGF-BB-bearing tumor cells and in colorectal adenocarcinoma, activated PDGF P-receptors do not colocalize with caveolin-1. Thus, growth factor receptors are segregated into specific cell membrane compartments that are preferentially activated through different mechanisms of ligand delivery, resulting in distinct biological endpoints. (Am J Pathol 2009, 175:171-189; DOI: 10.2353/ajpath.2009.080769)