title: Necdin controls EGFR signaling linked to astrocyte differentiation in primary cortical progenitor cells.
abstract: 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.
authors.affiliation: Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Fujimoto
authors.affiliation: Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Kazushiro
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Osaka, Japan. Electronic address: yoshikaw@protein.osaka-u.ac.jp.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D000072417:Protein Domains
chemical_list: D051380:GRB2 Adaptor Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C069766:necdin; D016222:Fibroblast Growth Factor 2; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: EGFR; ERK; Gliogenesis; MAGE family; Necdin