EphA2 is a functional receptor for the growth factor progranulin

J Cell Biol. 2016 Dec 5;215(5):687-703. doi: 10.1083/jcb.201603079. Epub 2016 Nov 30.

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.

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Capillaries / metabolism
  • Cell Membrane / metabolism
  • Enzyme Activation
  • Genes, Reporter
  • Green Fluorescent Proteins / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Morphogenesis
  • Progranulins
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, EphA2 / metabolism*
  • Signal Transduction
  • Solubility

Substances

  • Adaptor Proteins, Vesicular Transport
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • Green Fluorescent Proteins
  • Receptor, EphA2
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • sortilin