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C-TAK1 interacts with microphthalmia-associated transcription factor, Mitf, but not the related family member Tfe3

Toni Schwarz1, Sharlene Murphy, Chee Sohn

  • 1Division of Orthodontics, Department of Developmental and Surgical Sciences, University of Minnesota School of Dentistry, 515 Delaware St. SE, Minneapolis, MN 55455, USA.

Biochemical and Biophysical Research Communications
|March 11, 2010
PubMed

Insights

Microphthalmia-associated transcription factor (Mitf) nuclear translocation is crucial for osteoclast differentiation. This study reveals Tfe3 does not shuttle, and identifies Protein Phosphatase 2A as a key regulator of Mitf nuclear entry.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Microphthalmia-associated transcription factor (Mitf) is essential for osteoclast differentiation.
  • Mitf nuclear translocation is induced by M-CSF/RANKL signaling, regulated by 14-3-3 and C-TAK1.
  • The related transcription factor Tfe3's role in this process is unclear.

Purpose of the Study:

  • To investigate the role of Tfe3 in osteoclast differentiation.
  • To elucidate the regulatory mechanisms of Mitf nuclear translocation.
  • To identify novel factors involved in Mitf signaling.

Main Methods:

  • Western blotting to assess protein expression and localization.
  • Overexpression studies of C-TAK1 and Mitf mutants.
  • Analysis of gene expression, including Acp5.
  • Detection of Protein Phosphatase 2A activity.

Main Results:

  • Tfe3 does not translocate to the nucleus and does not interact with C-TAK1.
  • C-TAK1 overexpression inhibits Acp5 expression; kinase-dead C-TAK1 or non-interacting Mitf mutant increases Acp5 expression.
  • The catalytic subunit of Protein Phosphatase 2A is upregulated in response to M-CSF/RANKL signaling.

Conclusions:

  • Tfe3 does not appear to play a direct role in M-CSF/RANKL-induced nuclear translocation.
  • C-TAK1 kinase activity is critical for regulating Acp5 expression during osteoclast differentiation.
  • Protein Phosphatase 2A may dephosphorylate Mitf, facilitating its nuclear entry and subsequent gene regulation in osteoclasts.

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