Premium
Dorsomorphin stimulates neurite outgrowth in PC12 cells via activation of a protein kinase A‐dependent MEK‐ERK1/2 signaling pathway
Author(s) -
Kudo Tadaaki,
Kanetaka Hiroyasu,
Mizuno Kazutoshi,
Ryu Yasuhiro,
Miyamoto Yoshiyuki,
Nunome Shoko,
Zhang Ye,
Kano Mitsuhiro,
Shimizu Yoshinaka,
Hayashi Haruhide
Publication year - 2011
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2011.01556.x
Subject(s) - neurite , biology , microbiology and biotechnology , mapk/erk pathway , protein kinase a , signal transduction , mek inhibitor , mitogen activated protein kinase , bone morphogenetic protein 2 , kinase , bone morphogenetic protein , biochemistry , in vitro , gene
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.