Figure 5.

Summarizing model to explain the pathway how SIAH ubiquitin ligases influence migration, invasion, and proliferation according to our results. At low levels of active SIAH1 or SIAH2, p27 is present and inhibits phosphorylation of Rb via CDK inhibition. Non-phosphorylated Rb sequesters the E2F1 transcription factor and thereby inhibits stathmin expression. High levels of active SIAH1 and SIAH2 ligases induce ubiquitinylation of p27 and subsequent proteasomal degradation. Active CDKs phosphorylate Rb, inducing the release of E2F1 and stathmin expression. Stathmin depolymerizes microtubules, a prerequisite for increased migration, invasion, and proliferation.