title: Identification of PLXDC1 and PLXDC2 as the transmembrane receptors for the multifunctional factor PEDF.
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.
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Riki
authors.initials: R
authors.lastname: Kawaguchi
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Miki
authors.initials: M
authors.lastname: Kassai
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, United States.
authors.forename: Muayyad
authors.initials: M
authors.lastname: Al-Ubaidi
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Mariam
authors.initials: M
authors.lastname: Ter-Stepanian
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D008024:Ligands; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C510620:PLXDC1 protein, human; C558538:PLXDC2 protein, human
keywords: biochemistry; cell biology; human disease; membrane receptors; none; signal transduction