Neuronal guidance protein Netrin-1 induces differentiation in human embryonal carcinoma cells.
Pluripotent cells within embryonal carcinoma (EC) can differentiate in vivo or in vitro on treatment with specific agents. Differentiating EC cells express lower levels of stem cell-related genes, such as Cripto-1. We show that migration of human EC cells (NTERA/2 and NCCIT) can be reduced following treatment with the guidance molecule Netrin-1. Moreover, Netrin-1 treatment increased the levels of beta-III tubulin, glial filament acidic protein, Nestin, and gamma-aminobutyric acid and reduced the expressions of Cripto-1, Nanog, and Oct4 in EC cells. These Netrin-1-induced effects in the EC cells were mediated via binding of Netrin-1 to the Neogenin receptor and activation of SHP-2, resulting in increased levels of inactive phosphorylated c-src((Y527)). These results suggest that Netrin-1 can induce neuroectodermal-like differentiation of human EC cells by affecting c-src signaling via SHP-2 activation and regulation of Nanog, Oct4, and Cripto-1 expressions.
Mancino
Mario
M
Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, Maryland 20892, USA. mario.mancino@cro-m.eu
Esposito
Claudia
C
Watanabe
Kazuhide
K
Nagaoka
Tadahiro
T
Gonzales
Monica
M
Bianco
Caterina
C
Normanno
Nicola
N
Salomon
David S
DS
Strizzi
Luigi
L
D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054278:Embryonal Carcinoma Stem Cells / Q000187:drug effects* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000032:analysis; D058851:GPI-Linked Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000032:analysis; D009363:Neoplasm Proteins / Q000032:analysis; D009414:Nerve Growth Factors / Q000494:pharmacology*; D000075388:Netrin-1; D050814:Octamer Transcription Factor-3 / Q000032:analysis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*
D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C000617351:NTN1 protein, human; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C070636:TDGF1 protein, human; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D004815:Epidermal Growth Factor; D016392:Proto-Oncogene Proteins pp60(c-src); C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11