Specific activation of the p38 mitogen-activated protein kinase signaling pathway and induction of neurite outgrowth in PC12 cells by bone morphogenetic protein-2.
Bone morphogenetic protein (BMP)-2 has the capacity to induce the neuronal differentiation of PC12 cells. Unlike nerve growth factor, however, BMP-2 failed to induce the activation of the 41-/43-kDa mitogen-activated protein (MAP) kinase pathway in these cells. In contrast, BMP-2 characteristically induced the sustained activation of the p38 MAP kinase pathway. Pretreatment of PC12 cells with SB203580 inhibited the BMP-2-induced neurite outgrowth formation in a dose-dependent manner; this inhibition coincided well with the ability of SB203580 to inihibit the BMP-2-induced activation of the p38 MAP kinase pathway. Overexpression in PC12 cells of wild-type MAP kinase kinase (MKK)-6 enhanced the BMP-2-induced activation of p38 MAP kinase, whose activation correlated well with the ability of these cells to induce neurite outgrowth in response to BMP-2. Transient expression of kinase-negative forms of MKK3/6 inhibited the formation of neurite outgrowth in response to BMP-2. Furthermore, expression of constitutively active forms of MKK3/6 induced neurite outgrowth without BMP-2 stimulation, and SB203580 inhibited this induction. These results clearly indicate that activation of the p38 MAP kinase pathway is necessary for BMP-2-induced neuronal differentiation of PC12 cells. Our results also suggest that activation of the p38 MAP kinase pathway alone can induce the neuronal differentiation of PC12 cells.
Iwasaki
S
S
Laboratory of Cell Regulation, School of Pharmaceutical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8131, Japan.
Iguchi
M
M
Watanabe
K
K
Hoshino
R
R
Tsujimoto
M
M
Kohno
M
M
D000595:Amino Acid Sequence; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002454:Cell Differentiation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D016501:Neurites; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases
C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D016212:Transforming Growth Factor beta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580