Activation of E3 ubiquitin ligases through recruitment to activated receptors. (a) Ubiquitination of CXCR4 by ITCH. ITCH activity is inhibited as a result of the intramolecular interaction between the WW domain and the carboxy-terminal catalytic HECT domain. Upon agonist-mediated activation, CXCR4 becomes phosphorylated at Ser324 and Ser325 by an unknown kinase. This leads to the recruitment of the ITCH, through its WW domain, and consequent release of the inhibitory intramolecular interaction, allowing ubiquitination of the receptor. (b) Ubiquitination of the TGF-β receptor by the SMURF2-SMAD7 complex. SMURF2 activity is inhibited as a result of the intramolecular interaction between the amino-terminal C2 and the carboxy-terminal catalytic HECT domain. The interaction with SMAD7 NTD displaces the C2 domain of SMURF2 from the HECT domain and activates the ligase. The activated SMURF2-SMAD7 complex associates with activated TGF-β receptor complexes at the membrane via the displaced C2 domain, causing receptor ubiquitination.