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Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signaling.

Angela J Glading1, Mark H Ginsberg

  • 1Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. angela_glading@urmc.rochester.edu

Disease Models & Mechanisms
|December 17, 2009
PubMed
Summary

KRIT1 (CCM1) negatively regulates beta-catenin signaling. Loss of KRIT1 increases beta-catenin activity, leading to vascular lesions and enhancing susceptibility to intestinal tumors in mice.

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • KRIT1 (CCM1) is part of a complex involved in cerebral cavernous malformations (CCM).
  • Loss of function in KRIT1, CCM2, or PDCD10 (CCM3) causes CCM, affecting 0.5% of humans.
  • KRIT1 stabilizes beta-catenin at endothelial cell-cell junctions, downstream of Rap1 GTPase.

Purpose of the Study:

  • To investigate the role of Rap1 and KRIT1 in regulating beta-catenin signaling.
  • To determine the impact of KRIT1 deficiency on beta-catenin-driven pathologies in vivo and in vitro.
  • To explore the therapeutic potential of targeting KRIT1 in related diseases.

Main Methods:

  • Studied the effects of KRIT1 depletion on beta-catenin localization and VE-cadherin interactions in endothelial cells.
  • Investigated Rap1 activation's impact on beta-catenin signaling in confluent endothelial cells.
  • Assessed beta-catenin signaling and polyp formation in hemizygous Krit1-deficient mice (Krit1+/-) using the Apc(Min/+) model.

Main Results:

  • Endothelial KRIT1 depletion caused beta-catenin dissociation from VE-cadherin and nuclear accumulation, increasing transcription.
  • Rap1 activation inhibited beta-catenin signaling in confluent cells, requiring intact junctions and KRIT1.
  • KRIT1 depletion broadly increased beta-catenin signaling in epithelial cells and in vivo.
  • Hemizygous Krit1 deficiency significantly increased intestinal polyps in Apc(Min/+) mice, linked to elevated beta-catenin transcription.

Conclusions:

  • KRIT1 acts as a negative regulator of canonical beta-catenin signaling in both endothelial and epithelial cells.
  • Loss of KRIT1 function predisposes to beta-catenin-driven pathologies, including vascular lesions and intestinal adenomas.
  • Understanding KRIT1's role in beta-catenin regulation offers insights into CCM pathogenesis and potential therapeutic strategies.