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Ca2+/Calmodulin induces translocation of membrane-associated TSC2 to the nucleus where it suppresses CYP24A1

Machiko Kazami1, Tomoya Sakamoto1, Tsukasa Suzuki1

  • 1Department of Agricultural Chemistry, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo, Japan.

Bioscience, Biotechnology, and Biochemistry
|November 4, 2022
PubMed

Insights

Tuberous sclerosis complex 2 (TSC2) protein, when activated by calcium/calmodulin (Ca2+/CaM) signaling, moves to the nucleus. This movement suppresses vitamin D receptor (VDR) activity and target gene transcription.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Tuberous sclerosis complex 2 (TSC2) is a tumor suppressor protein crucial for regulating mechanistic target of rapamycin (mTOR) activity.
  • The interaction between TSC2 and calmodulin (CaM) is known to influence mTOR signaling, but its broader downstream effects are not fully understood.
  • Investigating novel roles of the CaM-TSC2 complex in cellular signaling pathways.

Purpose of the Study:

  • To elucidate downstream signaling pathways regulated by the CaM-TSC2 complex.
  • To determine the effect of Ca2+/CaM signaling on TSC2 localization and function.
  • To investigate the impact of the CaM-TSC2 complex on vitamin D receptor (VDR) transcriptional activity.

Main Methods:

  • Utilized rat brain and HeLa cells to study protein translocation.
  • Investigated Ca2+/CaM signaling activation and its effect on TSC2.
  • Assessed the transcriptional activity of VDR and its target gene, CYP24A1.
  • Analyzed the formation of transcriptional complexes involving TSC2.

Main Results:

  • Activation of Ca2+/CaM signaling induced the translocation of membrane-associated TSC2 to the nucleus.
  • TSC2 was released from the membrane in a CaM-dependent manner in both rat brain and HeLa cells.
  • The CaM-bound TSC2 formed a transcriptional complex that partially suppressed CYP24A1 gene transcription, a VDR target.
  • These findings indicate TSC2's role in attenuating VDR-mediated transcription.

Conclusions:

  • Ca2+/CaM signaling modulates TSC2 localization, promoting its nuclear entry.
  • TSC2, in a CaM-activated state, can interfere with VDR transcriptional regulation.
  • The CaM-TSC2 complex plays a role in suppressing the transcription of VDR target genes like CYP24A1.
Keywords:
CYP24A1CaMTSC2translocationvitamin D metabolism

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