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B-type Plexins promote the GTPase activity of Ran to affect androgen receptor nuclear translocation in prostate

Ritu Garg1, Sofia Endzhievskaya2, Magali Williamson3

  • 1School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Cancer Gene Therapy
|August 10, 2023
PubMed

Insights

B-type plexins act as GTPase activating proteins (GAPs) for Ran, regulating nuclear transport. This mechanism explains how prostate cancer becomes resistant to androgen deprivation therapy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Metastatic prostate cancer resistance to anti-androgen therapy is a significant clinical challenge.
  • PlexinB1, a receptor for Sema3C, is implicated in promoting resistance to androgen withdrawal.
  • The precise mechanism by which PlexinB1 facilitates androgen receptor (AR) nuclear translocation remains elusive.

Purpose of the Study:

  • To elucidate the mechanism by which PlexinB1 mediates nuclear translocation of the androgen receptor.
  • To investigate the role of PlexinB1 and PlexinB2 as regulators of nuclear import.
  • To determine if Plexins function as GTPase activating proteins (GAPs) for the RasGTPase Ran.

Main Methods:

  • Biochemical assays to test the GTPase activating protein (GAP) activity of purified PlexinB1/B2 on RanGTP.
  • Cellular assays involving PlexinB1/B2 depletion or activation with Sema4D to assess RanGTP levels.
  • Analysis of Ran-Plexin interactions and AR nuclear translocation.
  • Expression analysis of PlexinB1 and Ran.

Main Results:

  • PlexinB1 and PlexinB2 function as GTPase activating proteins (GAPs) for Ran, catalyzing RanGTP hydrolysis.
  • Mutations in the PlexinB1 GAP domain abolish its catalytic activity.
  • Activation of PlexinB1/B2 by Sema4D reduces cellular RanGTP levels, while depletion of PlexinB1/B2 increases RanGTP.
  • Ran directly binds to B-type plexins in a GTP-dependent manner.
  • Sema4D/PlexinB1-induced AR nuclear translocation is dependent on PlexinB1's GAP activity and Ran function.

Conclusions:

  • PlexinB1 and PlexinB2 act as RanGAPs, regulating nuclear import.
  • This RanGAP activity of Plexins contributes to the ligand-independent nuclear translocation of the androgen receptor.
  • Plexins may drive the progression of androgen-independent prostate cancer via their role in nuclear trafficking.

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