Figure 4.

Proposed model of the mechanism by which the misregulated expression of E2s, E3s and DUB's may contribute to tumorigenesis and metastasis. The information from the reports described in this review reveals that inhibition of E2s, E3s and DUB's with either small interfering RNA or small molecule inhibitors is sufficient to inhibit the progression and metastasis of tumors. However, some of these reports show that the misregulated expression of the members of the ubiquitination pathway occurs in multiple tumors. It is not clear whether a subpopulation of cells within a tumor, for instance, may rely on the misregulated expression of one member only or on a combination of the misregulated expression of these proteins to support aberrant oncogenic signaling. In addition, it is not clearly demonstrated whether the misregulated expression of E2s and E3s stabilizes oncogenic signaling via the catalysis of non-proteasomal ubiquitin linkages, while DUB's remove ubiquitin linkages that would otherwise lead to proteasomal degradation. Nevertheless, we describe a common conclusion from multiple reports that members of the ubiquitination pathway drive tumor aggressiveness and culminate in metastasis.