VHL and metastatic neoplasm: Alternatively, several proteins are known to specifically target and destabilize VHL: 1) E2-EPF ubiquitin carrier protein is another ubiquitin ligase component that directly targets VHL for proteasomal degradation and is expressed in primary and metastatic tumors (34); 2) casein kinase 2 destabilizes VHL through phosphorylation of serines 33, 38, and 43 and is upregulated in most human cancers (35); 3) transglutaminase 2 is a crosslinking enzyme that causes VHL degradation by polymerization and is also overexpressed in many cancers (36).