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

Abstract

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)-BB activates a cohort of PDGF-␤ receptors primarily confined to the lipid raft component of the cell membrane, specifically caveolae. In contrast, cellbound PDGF-BB delivered via cell-cell contact results in activation and the subsequent up-regulation of a cohort of PDGF ␤-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␤-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 ␤-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 ␤-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.

Soluble FLT1 Binds Lipid Microdomains in Podocytes to Control Cell Morphology and Glomerular Barrier Function

“…Utilizing a proteomics approach followed by colocalization studies, we identified a number of proteins that associate with sFLT1 at the cell surface. Intriguingly, two of the top hits, SCARB1 and ANXA2, are proteins known to associate with lipid rafts-subdomains involved in podocyte actin dynamics and in cytoskeletal reorganization in other pericyte populations (Simons et al, 2001;Sundberg et al, 2009). Along with their location in lipid rafts, these proteins were of interest for other reasons.…”

Brain Pericytes: Emerging Concepts and Functional Roles in Brain Homeostasis

“…These receptors were activated by soluble PDGF-B and membrane-bound PDGF-B, which mediate distinct cellular functions. Cytoskeletal reorganization was only induced by soluble PDGF-B (Sundberg et al 2009). The recruitment of pericytes may be determined by the signal balance between the PDGF-B concentration gradient and the localization of PDGFR-b on the cell membrane.…”

Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells

“…The antiproliferative activity of tacalcitol (Tac), calcipotriol (Cal) and 1a,25(OH) 2 D 3 (1a,25) in T98G cells, measured by manual cell counting. The growth-inhibitory effects were dose-dependent, with the strongest effect at 10 lM.…”