Journal
MOLECULAR CELL
Volume 46, Issue 1, Pages 67-78Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2012.02.005
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Funding
- Pew Charitable Trust
- International Human Frontier Science Program Organization
- ALSAC
- Public Health Service [5P30CA021765, RO1GM069530, RO1GM077053, RO1CA93804, RO1CA63113, PO1CA050661]
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Fbw7, a substrate receptor for Cul1-RING-ligase (CRL1), facilitates the ubiquitination and degradation of several proteins, including Cyclin E and c-Myc. In spite of much effort, the mechanisms underlying Fbw7 regulation are mostly unknown. Here, we show that Glomulin (Glmn), a protein found mutated in the vascular disorder glomuvenous malformation (GVM), binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity. Loss of Glmn in a variety of cells, tissues, and GVM lesions results in decreased levels of Fbw7 and increased levels of Cyclin E and c-Myc. The increased turnover of Fbw7 is dependent on CRL and proteasome activity, indicating that Glmn modulates the E3 activity of CRL1(Fbw7). These data reveal an unexpected functional connection between Glmn and Rbx1 and demonstrate that defective regulation of Fbw7 levels contributes to GVM.
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