Because we observed that (1) c-Cbl promoted P4D1-specific Ub signals on activated EGFR; (2) VHL-dependent poly-ubiquitylation on EGFR was c-Cbl independent; (3) c-Cbl loss and lysosome inhibition had very similar effects on EGFR stability in ccRCC cells; (4) proteasome inhibitors, not lysosome inhibitors, abolished the EGFR stability differences in VHL-expressing and VHL-deficient cells, it was likely that pVHL-containing E3 complex and c-Cbl promoted different kinds of ubiquitylation on activated EGFR. Here, VHL is linked to nonpapillary renal cell carcinoma.