Abstract
Pigment Epithelium Derived Factor (PEDF) is a secreted factor that has broad biological activities. It was first identified as a neurotrophic factor and later as the most potent natural antiangiogenic factor, a stem cell niche factor, and an inhibitor of cancer cell growth. Numerous animal models demonstrated its therapeutic value in treating blinding diseases and diverse cancer types. A long-standing challenge is to reveal how PEDF acts on its target cells and the identities of the cell-surface receptors responsible for its activities. Here we report the identification of transmembrane proteins PLXDC1 and PLXDC2 as cell-surface receptors for PEDF. Using distinct cellular models, we demonstrate their cell type-specific receptor activities through loss of function and gain of function studies. Our experiments suggest that PEDF receptors form homooligomers under basal conditions, and PEDF dissociates the homooligomer to activate the receptors. Mutations in the intracellular domain can have profound effects on receptor activities.
Highlights
Employing physiological pathways to impede pathological processes has been a fruitful approach in developing effective therapeutics for human disease
We found that expression of plexin domain containing 1 (PLXDC1) or plexin domain containing 2 (PLXDC2) confers extracellular Pigment Epithelium Derived Factor (PEDF) binding to live cells (Figure 1A–C)
We found that PEDF—mediated cell death was completely suppressed by siRNA-mediated knockdown of PLXDC2, but there was no suppression by siRNA knockdown of PLXDC1 (Figure 3A and Figure 3—figure supplement 1)
Summary
Employing physiological pathways to impede pathological processes has been a fruitful approach in developing effective therapeutics for human disease. There exists a natural factor that can inhibit pathogenesis of several major diseases and has surprisingly diverse therapeutic value This factor is called Pigment Epithelium-Derived Factor (PEDF) (Dawson et al, 1999; Tombran-Tink and Barnstable, 2003) and was originally identified as a strong protective factor for neurons (Tombran-Tink and Barnstable, 2003). PEDF inhibits endothelial cell migration and angiogenesis even in the presence of strong proangiogenic factors (Dawson et al, 1999) It targets new vessel growth without affecting pre-existing vessels.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
