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RAPGEF5 Regulates Nuclear Translocation of β-Catenin

John N Griffin1, Florencia Del Viso2, Anna R Duncan2

  • 1Pediatric Genomics Discovery Program, Departments of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK.

Developmental Cell
|January 2, 2018
PubMed

Insights

RAPGEF5 regulates embryonic left-right patterning through Wnt signaling by controlling beta-catenin nuclear transport. This novel pathway bypasses traditional mechanisms, offering new therapeutic targets for diseases linked to Wnt signaling.

Area of Science:

  • Developmental Biology
  • Molecular Signaling
  • Genetics

Background:

  • Canonical Wnt signaling is crucial for embryonic development.
  • Dysregulated Wnt signaling is implicated in congenital malformations and cancer.
  • Nuclear localization of beta-catenin is key to Wnt pathway activation, but its transport mechanism is unclear.

Purpose of the Study:

  • To investigate the role of RAPGEF5 in Wnt signaling and embryonic development.
  • To elucidate the mechanism of beta-catenin nuclear transport.
  • To identify novel therapeutic targets for Wnt-related diseases.

Main Methods:

  • Identified RAPGEF5 in a patient with congenital heart disease and heterotaxy.
  • Studied RAPGEF5's effect on left-right patterning via Wnt signaling.
  • Investigated beta-catenin nuclear translocation independent of known pathways.

Main Results:

  • RAPGEF5 regulates left-right patterning through Wnt signaling.
  • RAPGEF5 mediates beta-catenin nuclear translocation independently of cytoplasmic stabilization and importin beta1/Ran.
  • A novel pathway involving RAPGEF5 activating Rap1a/b GTPases for beta-catenin nuclear transport is proposed.

Conclusions:

  • RAPGEF5 defines a parallel pathway for beta-catenin nuclear transport.
  • This discovery provides new insights into Wnt signaling regulation.
  • Results suggest potential therapeutic strategies for Wnt-related diseases.
Keywords:
GTPaseRAPGEF5Ran independentRapWnt signalingXenopuscongenital heart diseaseheterotaxynuclear transportβ-catenin

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