Dorsomorphin stimulates neurite outgrowth in PC12 cells via activation of a protein kinase A-dependent MEK-ERK1/2 signaling pathway

Tadaaki Kudo, Hiroyasu Kanetaka, Kazutoshi Mizuno, Yasuhiro Ryu, Yoshiyuki Miyamoto, Shoko Nunome, Ye Zhang, Mitsuhiro Kano, Yoshinaka Shimizu, Haruhide Hayashi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

In this study, we investigated the effect of dorsomorphin, a selective inhibitor of bone morphogenetic protein (BMP) signaling, on rat PC12 pheochromocytoma cell differentiation. PC12 cells can be induced to differentiate into neuron-like cells possessing elongated neurites by nerve growth factor, BMP2, and other inducers. Cells were incubated with BMP2 and/or dorsomorphin, and the extent of neurite outgrowth was evaluated. Unexpectedly, BMP2-mediated neuritogenesis was not inhibited by co-treatment with dorsomorphin. We also found that treatment with dorsomorphin alone, but not another BMP signaling inhibitor, LDN-193189, induced neurite outgrowth in PC12 cells. To further understand the mechanism of action of dorsomorphin, the effects of this drug on intracellular signaling were investigated using the following signaling inhibitors: the ERK kinase (MEK) inhibitor U0126; the tropomyosin-related kinase A inhibitor GW441756; and the protein kinase A (PKA) inhibitor H89. Dorsomorphin induced rapid and sustained ERK1/2 activation; however, dorsomorphin-mediated ERK1/2 activation and neuritogenesis were robustly inhibited in the presence of U0126 or H89, but not GW441756. These findings suggest that dorsomorphin has the potential to induce neuritogenesis in PC12 cells, a response that requires the activation of PKA-dependent MEK-ERK1/2 signaling.

Original languageEnglish
Pages (from-to)1121-1132
Number of pages12
JournalGenes to Cells
Volume16
Issue number11
DOIs
Publication statusPublished - 2011 Nov 1

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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