Specific Activation of the p38 Mitogen-activated Protein Kinase Signaling Pathway and Induction of Neurite Outgrowth in PC12 Cells by Bone Morphogenetic Protein-2

• Published in: The Journal of biological chemistry 1999-09, Vol.274 (37), p.26503-26510
• Main Authors: Iwasaki, Shoji, Iguchi, Makoto, Watanabe, Kazushi, Hoshino, Rika, Kohno, Michiaki, Tsujimoto, Masafumi
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Differentiation; Enzyme Activation; Enzyme Inhibitors - pharmacology; Imidazoles - pharmacology; Mitogen-Activated Protein Kinases; Molecular Sequence Data; Neurites; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; p38 Mitogen-Activated Protein Kinases; PC12 Cells; Pyridines - pharmacology; Rats; Transforming Growth Factor beta
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.37.26503

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.