Abstract
The function of tumor suppressor VHL is compromised in the vast majority of clear cell renal cell carcinoma, and its mutations or loss of expression was causal for this disease. pVHL was found to be a substrate recognition subunit of an E3 ubiquitin ligase, and most of the tumor-derived mutations disrupt this function. pVHL was found to bind to the alpha subunits of hypoxia-inducible factor (HIF) and promote their ubiquitination and proteasomal degradation. Proline hydroxylation on key sites of HIFα provides the binding signal for pVHL E3 ligase complex. Beside HIFα, several other VHL targets have been identified, including activated epidermal growth factor receptor (EGFR), RNA polymerase II subunits RPB1 and hsRPB7, atypical protein kinase C (PKC), Sprouty2, β-adrenergic receptor II, and Myb-binding protein p160. HIFα is the most well studied substrate and has been proven to be critical for pVHL’s tumor suppressor function, but the activated EGFR and PKC and other pVHL substrates might also be important for tumor growth and drug response. Their regulations by pVHL and their relevance to signaling and cancer are discussed.
Highlights
SUMMARY Proline hydroxylation on HIFα proteins led to their recognition by pVHL, followed by very efficient ubiquitination and proteasomal degradation
Proline hydroxylation on RPB1, SPRY2, and β2AR led to pVHL-dependent ubiquitination, this did not automatically cause protein degradation as the ubiquitin chain linkages on them might be different
It is unclear whether SPRY2 and β2AR are more abundant in VHL-defective renal cancer cells and whether they contribute to tumor growth or maintenance at all
Summary
Prominent features even when the oxygen supply is not limited. In the xenograft models of ccRCC, constitutive HIF activation was both sufficient (Kondo et al, 2002) and necessary for tumor growth (Kondo et al, 2003; Zimmer et al, 2004). As Rabaptin-5 was critical for Rab5-mediated endosome fusion, reduced expression of Rabaptin-5 led to delayed EGFR sorting to the late endosome and lysosome, and this led to longer half-lives of the activated EGFR This explanation predicted that delayed turnover of activated EGFR in VHL-defective ccRCC cells was due to high levels of HIF α subunits. Zhou and Yang (2011) found that the endogenous HIF was not the only or major cause of delayed EGFR turnover in VHL-defective ccRCC cells They found that pVHL-mediated downregulation of the activated EGFR was mostly mediated by proteasome instead of lysosome. While wild type pVHL could promote the degradation of PKCζII efficiently, some tumorderived VHL mutants (such as Y98H, C162W, and R167W) failed to do so It remained unclear whether PKCζII was a direct substrate for pVHL complex, and whether proline hydroxylation played a role in the turnover of PKCζII. The active form of PKCλ bound to pVHL tighter than its wild type www.frontiersin.org
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