Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7.
BACKGROUND
BMP2 is known to play a wide variety of roles, including some in the development of the nervous system. This cytokine has been reported to induce neurite outgrowth in rat pheochromocytoma PC12 cells via the activation of a p38 MAP kinase, although its regulatory mechanism remains largely to be elucidated.


RESULTS
BMP2-induced neurite outgrowth in PC12 cells was inhibited by the introduction of a kinase-negative form of a MAP kinase kinase kinase, TAK1, an upstream regulatory kinase for p38 kinase. Following BMP2 stimulation, the expression of Smad6 and Smad7, inhibitory Smad species that are known to inhibit the BMP2-restricted Smad species, Smad1, Smad5 and Smad8, was up-regulated. Unexpectedly, over-expression of either Smad6 or Smad7 in PC12 cells repressed the BMP2-induced neurite outgrowth and severely impeded the p38 kinase pathway. Both of these inhibitory Smads were found to interact physically with TAK1-binding protein, a molecule required for TAK1 activation.


CONCLUSIONS
This study demonstrates that BMP2-induced neurite outgrowth in PC12 cells involves activation of the TAK1-p38 kinase pathway which is inhibited by Smad6 and Smad7.
Yanagisawa
M
M
Department of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Nakashima
K
K
Takeda
K
K
Ochiai
W
W
Takizawa
T
T
Ueno
M
M
Takizawa
M
M
Shibuya
H
H
Taga
T
T
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D016716:PC12 Cells; D011494:Protein Kinases / Q000494:pharmacology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000378:metabolism / Q000494:pharmacology*; D016212:Transforming Growth Factor beta; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7
D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D015699:HIV Envelope Protein gp120; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C525720:Bmp2 protein, rat; C497804:Smad6 protein, rat; C497808:Smad7 protein, rat