title: EphA2 is a functional receptor for the growth factor progranulin.
abstract: Although the growth factor progranulin was discovered more than two decades ago, the functional receptor remains elusive. Here, we discovered that EphA2, a member of the large family of Ephrin receptor tyrosine kinases, is a functional signaling receptor for progranulin. Recombinant progranulin bound with high affinity to EphA2 in both solid phase and solution. Interaction of progranulin with EphA2 caused prolonged activation of the receptor, downstream stimulation of mitogen-activated protein kinase and Akt, and promotion of capillary morphogenesis. Furthermore, we found an autoregulatory mechanism of progranulin whereby a feed-forward loop occurred in an EphA2-dependent manner that was independent of the endocytic receptor sortilin. The discovery of a functional signaling receptor for progranulin offers a new avenue for understanding the underlying mode of action of progranulin in cancer progression, tumor angiogenesis, and perhaps neurodegenerative diseases.
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.|Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Thomas
authors.initials: T
authors.lastname: Neill
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.|Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Simone
authors.identifier: http://orcid.org/0000-0002-4233-7627
authors.initials: S
authors.lastname: Buraschi
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.|Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Atul
authors.initials: A
authors.lastname: Goyal
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.|Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sharpe
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.|Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Elizabeth
authors.identifier: http://orcid.org/0000-0001-5422-9474
authors.initials: E
authors.lastname: Natkanski
authors.affiliation: Institute of Pharmacology and Toxicology, Goethe University, Frankfurt am Main 60323, Germany.
authors.forename: Liliana
authors.identifier: http://orcid.org/0000-0002-3318-3005
authors.initials: L
authors.lastname: Schaefer
authors.affiliation: Department of Urology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.|Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0002-2319-7884
authors.initials: A
authors.lastname: Morrione
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107 renato.iozzo@jefferson.edu.|Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D002196:Capillaries / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009024:Morphogenesis; D000077153:Progranulins; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D036104:Receptor, EphA2 / Q000378:metabolism*; D015398:Signal Transduction; D012995:Solubility; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D049452:Green Fluorescent Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D000077153:Progranulins; D051057:Proto-Oncogene Proteins c-akt; D036104:Receptor, EphA2; D000099183:Sortilin; C492314:GRN protein, human