Regulation of E3 activities by post-translational modifications. A) Extracellular stimuli can induce various post-translational modifications of E3 ligases. This might result on a positive or a negative regulation of the ligase activity. Examples are reported (see main text for detailed explanations). The arrows represent the integration of numerous signals. pY, tyrosine phosphorylation; pS/T, serine or threonine phosphorylation; Ub, ubiquitination; Ub-like, neddylation or sumoylation. B) Comparison between the phospho-based network and the Ub-based network. Similarity includes recognition by dedicated protein domains (SH2 and UIM are example), inducibility by upstream signals and reversibility (DUBs work as phosphatases). In addition, kinases are often activated by tyrosine phosphorylation in the signalling cascade while E3 ligases could be activated by ubiquitination.