title: The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Adriana E
authors.initials: AE
authors.lastname: Tron
authors.forename: Takehiro
authors.initials: T
authors.lastname: Arai
authors.forename: David M
authors.initials: DM
authors.lastname: Duda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuwabara
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Olszewski
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Bahamon
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Schulman
authors.forename: James A
authors.initials: JA
authors.lastname: DeCaprio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005918:Glomus Tumor / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010236:Paraganglioma, Extra-Adrenal / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C103024:GLMN protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C479529:RBX1 protein, human; D044767:Ubiquitin-Protein Ligases