Inhibition of BMP2‐induced, TAK1 kinase‐mediated neurite outgrowth by Smad6 and Smad7

  title={Inhibition of BMP2‐induced, TAK1 kinase‐mediated neurite outgrowth by Smad6 and Smad7},
  author={Makoto Yanagisawa and Kinichi Nakashima and Kunitoshi Takeda and Wataru Ochiai and Takumi Takizawa and Masaya Ueno and Makiko Takizawa and Hiroshi Shibuya and Tetsuya Taga},
  journal={Genes to Cells},
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. 

Transforming Growth Factor-β1 (TGF-β)–induced Apoptosis of Prostate Cancer Cells Involves Smad7-dependent Activation of p38 by TGF-β-activated Kinase 1 and Mitogen-activated Protein Kinase Kinase 3

The inhibitory Smad7, a direct target gene for transforming growth factor-β (TGF-β), mediates TGF-β1–induced apoptosis in several cell types. Herein, we report that apoptosis of human prostate canc...

Mechanisms for TGF-β-Mediated Regulation of the Actin Filament System and Apoptosis

Transforming growth factor-β (TGF-β) is a member of a large superfamily of cytokines which participate in many different types of cellular processes, such as growth inhibition, cell migration, diff

Non-Smad Signaling Pathways of the TGF-β Family.

  • Ying E. Zhang
  • Biology, Chemistry
    Cold Spring Harbor perspectives in biology
  • 2017
This review summarizes the current knowledge of the mechanisms by which non-Smad signaling pathways are directly activated in response to ligand binding, how activation of these pathways impinges on Smads and non- Smad targets, and how final cellular responses are affected in Response to these noncanonical signaling modes.

Nerve growth factor mediates activation of the Smad pathway in PC12 cells.

It is found that rat pheochromocytoma cells, which represent a model system for neuronal differentiation, are unresponsive to TGF-beta1 due to limiting levels of its receptor, TbetaRII, however, stimulation with nerve growth factor leads to activation of the Smad pathway independent of T GF-beta.

Interplays Between The Smad and Map Kinase Signaling Pathways

How mitogen-activated protein kinases (MAPKs) modify the outcome of Smad activation by TGF-β is described, and how crosstalk mechanisms between the Smad and MAPK pathways take place and affect cellular behavior and T GF-β target gene expression is described.

Transforming Growth Factor-β-activated Kinase-1 (TAK1), a MAP3K, Interacts with Smad Proteins and Interferes with Osteogenesis in Murine Mesenchymal Progenitors*[boxs]

It is suggested that TAK1 is a factor that is involved in the fine-tuning of BMP effects during osteogenic development that interferes with R-Smad transactivation in reporter assays and affects subcellular distribution of Smad proteins.

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

It is suggested that dorsomorphin has the potential to induce neuritogenesis in PC12 cells, a response that requires the activation of PKA‐dependent MEK‐ERK1/2 signaling.



BMP2-induced Apoptosis Is Mediated by Activation of the TAK1-p38 Kinase Pathway That Is Negatively Regulated by Smad6*

It is demonstrated that BMP2 dose-dependently induces apoptosis in MH60 cells even in the presence of IL-6, and it is shown that MH60-derived transfectants expressing Smad6 are resistant to the apoptotic signal of BMP1, suggesting that Smad 6 is likely to function as a negative regulator of the TAK1 pathway in the B MP2 signaling, in addition to the previously reported Smad pathway.

Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300.

The formation of a complex between STAT3 and Smad1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neural progenitors.

Smurf1 Interacts with Transforming Growth Factor-β Type I Receptor through Smad7 and Induces Receptor Degradation*

It is shown that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and inducesSmad7 ubiquitination and translocation into the cytoplasm, revealing a novel function of Smad 7, i.e. induction of degradation of TβR-I through recruitment of an E 3 ligase to the receptor.

Induction of Smad6 mRNA by bone morphogenetic proteins.

It is shown that expression of the Smad6 mRNA is dramatically induced by BMP-2 or osteogenic protein-1 (OP-1)/BMP-7 in various cells, indicating that Smad 6 may form a feedback loop to regulate the signaling activity of BMPs.

XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1–TAK1 in the BMP signaling pathway

Results suggest that XIAP participates in the BMP signaling pathway as a positive regulator linking the B MP receptors and TAB1–TAK1, involved in mesoderm induction and patterning in early Xenopus embryos.

TGF-β signalling from cell membrane to nucleus through SMAD proteins

Inhibitory SMADs have been identified that block the activation of these pathway-restricted SMADS that direct transcription to effect the cell's response to TGF-β.

Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members.

The isolation of human Smad6 is reported, which is closely related to Smad7, to show that expression of inhibitory Smads is induced by multiple stimuli, including the various TGF-beta family members, whose action they antagonize.

Membrane targeting of p21‐activated kinase 1 (PAK1) induces neurite outgrowth from PC12 cells

It is shown that the extension of neurites induced by nerve growth factor (NGF) in the neuronal cell line PC12 is inhibited by dominant‐negative Rac2 and Cdc42, indicating that these GTPases are required components of the NGF signaling pathway.

Smad6 Is a Smad1/5-induced Smad Inhibitor

Results indicate that the expression of Smad6 is regulated by the effects of BMP-activated Smad1/5 on the Smad 6promoter, and this activation was enhanced by cotransfection of B MP-responsive Smads, i.e. Smad 1 or Smad5.

TAB1: An Activator of the TAK1 MAPKKK in TGF-β Signal Transduction

Overproduction of TAB1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by TGF-β, and increased the kinase activity of TAK1.