NEDD8 acts as a 'molecular switch' defining the functional selectivity of VHL.
The von Hippel-Lindau (VHL) tumour suppressor protein is important in the E3 ubiquitin ligase ECV (Elongin B/C-CUL2-VHL)-mediated destruction of hypoxia-inducible factor and the promotion of fibronectin (FN) extracellular matrix assembly. Although the precise molecular mechanism controlling the selectivity of VHL function remains unknown, a failure in either process is associated with oncogenic progression. Here, we show that VHL performs its FN-associated function independently of the ECV complex, highlighting the autonomy of these pathways. Furthermore, we show that NEDD8, a ubiquitin-like molecule, acts as a 'molecular switch' in which its covalent conjugation to VHL prohibits the engagement of the scaffold component CUL2 and, concomitantly, activates the association with FN. These findings provide the first mechanistic step in defining the functional selectivity of VHL and explain a previously unrecognized function of NEDD8.
Russell
Ryan C
RC
Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
Ohh
Michael
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D044842:Cullin Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D008113:Liver Neoplasms / Q000473:pathology; D008958:Models, Molecular; D000075687:NEDD8 Protein; D012516:Osteosarcoma / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D000911:Antibodies, Monoclonal; C105153:CUL2 protein, human; D044842:Cullin Proteins; D005353:Fibronectins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D034741:RNA, Small Interfering; D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein