Necdin controls EGFR signaling linked to astrocyte differentiation in primary cortical progenitor cells

Cell Signal. 2016 Feb;28(2):94-107. doi: 10.1016/j.cellsig.2015.11.016. Epub 2015 Dec 2.


Cellular signaling mediated by the EGF receptor (EGFR) plays a key role in controlling proliferation and differentiation of cortical progenitor cells (CPCs). However, regulatory mechanisms of EGFR signaling in CPCs remain largely unknown. Here we demonstrate that necdin, a MAGE (melanoma antigen) family protein, interacts with EGFR in primary CPCs and represses its downstream signaling linked to astrocyte differentiation. EGFR was autophosphorylated and interacted with necdin in EGF-stimulated CPCs. Necdin bound to autophosphorylated EGFR via its tyrosine kinase domain. EGF-induced phosphorylation of ERK was enhanced in necdin-null CPCs, where the interaction between EGFR and the adaptor protein Grb2 was strengthened, suggesting that endogenous necdin suppresses the EGFR/ERK signaling pathway in CPCs. In necdin-null CPCs, astrocyte differentiation induced by the gliogenic cytokine cardiotrophin-1 was significantly accelerated in the presence of EGF, and inhibition of EGFR/ERK signaling abolished the acceleration. Furthermore, necdin strongly suppressed astrocyte differentiation induced by overexpression of EGFR or its ligand binding-defective mutant equivalent to a glioblastoma-associated EGFR variant. These results suggest that necdin acts as an intrinsic suppressor of the EGFR/ERK signaling pathway in EGF-responsive CPCs to restrain astroglial development in a cell-autonomous manner.

Keywords: EGFR; ERK; Gliogenesis; MAGE family; Necdin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / enzymology
  • Astrocytes / metabolism*
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology*
  • Cerebral Cortex / enzymology
  • Cerebral Cortex / metabolism
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblast Growth Factor 2 / pharmacology
  • GRB2 Adaptor Protein / antagonists & inhibitors
  • GRB2 Adaptor Protein / metabolism
  • MAP Kinase Signaling System*
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / enzymology
  • Neural Stem Cells / metabolism*
  • Nuclear Proteins / metabolism*
  • Protein Domains


  • GRB2 Adaptor Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • necdin
  • Fibroblast Growth Factor 2
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases