Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signaling.
KRIT1, also called CCM1, is a member of a multiprotein complex that contains the products of the CCM2 and PDCD10 (also known as CCM3) loci. Heterozygous loss of any of the genes that encode these proteins leads to cerebral cavernous malformations (CCM), which are vascular lesions that are found in around 0.5% of humans. KRIT1 mediates the stabilization of beta-catenin-containing endothelial cell-cell junctions downstream of the Rap1 GTPase. Here, we report that Rap1 and KRIT1 are negative regulators of canonical beta-catenin signaling in mice and that hemizygous Krit1 deficiency exacerbates beta-catenin-driven pathologies. Depletion of endothelial KRIT1 caused beta-catenin to dissociate from vascular endothelial (VE)-cadherin and to accumulate in the nucleus with consequent increases in beta-catenin-dependent transcription. Activation of Rap1 inhibited beta-catenin-dependent transcription in confluent endothelial cells; this effect required the presence of intact cell-cell junctions and KRIT1. These effects of KRIT1 were not limited to endothelial cells; the KRIT1 protein was expressed widely and its depletion increased beta-catenin signaling in epithelial cells. Moreover, a reduction in KRIT1 expression also increased beta-catenin signaling in vivo. Hemizygous deficiency of Krit1 resulted in a ~1.5-fold increase in intestinal polyps in the Apc(Min/+) mouse, which was associated with increased beta-catenin-driven transcription. Thus, KRIT1 regulates beta-catenin signaling, and Krit1(+/-) mice are more susceptible to beta-catenin-driven intestinal adenomas.
Glading
Angela J
AJ
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. angela_glading@urmc.rochester.edu
Ginsberg
Mark H
MH
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology; D000075927:KRIT1 Protein; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D015820:Cadherins; D000075927:KRIT1 Protein; C491535:Krit1 protein, mouse; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; D020827:rap1 GTP-Binding Proteins