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YWK-II/APLP2 inhibits TGF-β signaling by interfering with the TGFBR2-Hsp90 interaction

Amannisa Tuersuntuoheti1, Qinshan Li2, Yu Teng1

  • 1Department of Biochemistry and Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.

Biochimica Et Biophysica Acta. Molecular Cell Research
|July 21, 2023
PubMed

Insights

YWK-II/APLP2 inhibits transforming growth factor-β (TGF-β) signaling by promoting the degradation of TGF-β type II receptors (TGFBR2). High YWK-II/APLP2 levels may antagonize TGF-β

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Biology

Background:

  • Transforming growth factor-β (TGF-β) signaling is crucial for cellular processes and often deregulated in malignancies.
  • TGF-β signaling involves TGF-β type I and type II receptors (TGFBR1 and TGFBR2), stabilized by Hsp90.
  • Inactivation of TGF-β signaling in cancer is frequently linked to TGFBR2 deregulation, but mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of YWK-II/APLP2 in regulating TGF-β signaling.
  • To elucidate the molecular mechanisms by which YWK-II/APLP2 affects TGFBR2 stability and function.

Main Methods:

  • Investigated YWK-II/APLP2's effect on TGFBR2 protein levels and TGF-β signaling.
  • Utilized knockdown and overexpression of YWK-II/APLP2.
  • Examined YWK-II/APLP2's interaction with TGFBR2 and Hsp90.
  • Assessed TGFBR2 ubiquitination and degradation.

Main Results:

  • YWK-II/APLP2 inhibits TGF-β signaling by promoting TGFBR2 degradation.
  • Knockdown of YWK-II/APLP2 increases TGFBR2 levels and sensitizes cells to TGF-β.
  • Overexpression of YWK-II/APLP2 destabilizes TGFBR2 and desensitizes cells.
  • YWK-II/APLP2 interferes with the TGFBR2-Hsp90 interaction, leading to enhanced ubiquitination and degradation.

Conclusions:

  • YWK-II/APLP2 negatively regulates the duration and intensity of TGF-β/Smad signaling.
  • Aberrant YWK-II/APLP2 expression in malignancies may counteract TGF-β-mediated growth inhibition.
  • YWK-II/APLP2 plays a role in carcinogenesis by disrupting TGF-β signaling.
Keywords:
Hsp90Receptor degradationTGF-β signalingTGFBR2YWK-II/APLP2

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