Abstract
The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of a ubiquitin ligase complex containing elongin B, elongin C, cullin 2, and Rbx1, which acts as a negative regulator of hypoxia inducible factor (HIF). VHL ubiquitinates and degrades the alpha subunits of HIF, and this is proposed to suppress tumorigenesis and tumor angiogenesis. Several lines of evidence also suggest important roles for HIF-independent VHL functions in the maintenance of primary cilium, extracellular matrix formation, and tumor suppression. We undertook a series of proteomic analyses to gain a comprehensive picture of the VHL-interacting proteins. We found that the ARF tumor suppressor interacts with VHL30, a longer VHL isoform, but not with VHL19, a shorter VHL isoform. ARF was found to release VHL30 from the E3 ligase complex, promoting the binding of VHL30 to a protein arginine methyltransferase, PRMT3. Our analysis of the VHL19 interactome also uncovered that VHL19 displays an affinity to collagens and their biosynthesis enzymes.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Arginine / metabolism
-
Cell Line, Tumor
-
Collagen / biosynthesis
-
Collagen / metabolism
-
Cullin Proteins / metabolism
-
Elongin
-
HEK293 Cells
-
Humans
-
Methylation
-
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / metabolism
-
Protein Binding
-
Protein Interaction Mapping*
-
Protein Isoforms / metabolism
-
Protein-Arginine N-Methyltransferases / metabolism*
-
Proteomics
-
Transcription Factors / metabolism
-
Tumor Suppressor Protein p14ARF / metabolism*
-
Tumor Suppressor Protein p53 / metabolism
-
Ubiquitin-Protein Ligase Complexes / metabolism
-
Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
Substances
-
CUL2 protein, human
-
Cullin Proteins
-
ELOB protein, human
-
ELOC protein, human
-
Elongin
-
Protein Isoforms
-
TP53 protein, human
-
Transcription Factors
-
Tumor Suppressor Protein p14ARF
-
Tumor Suppressor Protein p53
-
Collagen
-
Arginine
-
Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
-
PRMT3 protein, human
-
Protein-Arginine N-Methyltransferases
-
Ubiquitin-Protein Ligase Complexes
-
Von Hippel-Lindau Tumor Suppressor Protein