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.
Many cells in our body release signals that trigger responses in other cells. A protein called PEDF is a signal released from a variety of cells that can prevent the formation of new blood vessels, protect cells in the retina and brain from damage and stop cancer cells from growing. Experiments using model animals have also demonstrated that PEDF could be used to treat a variety of eye diseases that lead to blindness and many types of cancer.
PEDF is found in tissues including the brain, eye, liver, heart and lung, but it was not known how cells sense this signal. Cells are expected to have specific proteins called receptors on the cell surface membrane to detect PEDF and transmit the signal into the cell; however, the identity of these receptors has remained a long-standing unsolved puzzle.
Cheng, Zhong, Kawaguchi et al. have now identified two human proteins that act as receptors for PEDF. These proteins—known as PLXDC1 and PLXDC2—span the cell surface membrane, and bind to PEDF on the outside of the cell. PLXDC1 and PLXDC2 are expressed on different types of cells that respond to PEDF. Furthermore, PEDF was unable to act upon cells that had been engineered to make less of these two receptors.
This study also revealed that each receptor can play different roles in different cell types. For example, exposing one type of cell from blood vessels to PEDF would normally kill them, but cells without PLXDC2 (but not those without PLXDC1) could survive PEDF treatment. Furthermore, PEDF treatment protects a type of neuron against environmental damage, and this activity depends on PLXDC1, but not PLXDC2.
How do the receptors transmit the PEDF signal from the outside of the cell to the inside of the cell? Cheng, Zhong, Kawaguchi et al. found that when PEDF is not present, both PLXDC1 and PLXDC2 form complexes containing more than one copy of either receptor. When PEDF binds to the receptors, it causes these complexes to disassemble and this activates further downstream signaling events inside the cell.
Understanding PEDF receptors and their mechanisms will open the way to developing new drugs that target these receptors to treat human diseases.