Figure 3

Schematic representation of ITCH self-ubiquitination and its involvement in crosstalk between Raf/MEK/ERK and Raf/MST2/LATS1/YAP signalling. Ubiquitin ligase activity of ITCH is negatively regulated by Fyn-mediated tyrosine phosphorylation but positively by JNK-mediated serine/threonine phosphorylation. The MST2/LATS1/YAP signalling cascade is triggered by RASSF1A as a result of a balancing act between RASSF1A-MST2 and MST2-Raf-1 complexes. Akt-mediated phosphorylation of YAP leads to its sequestration by 14-3-3. Active YAP translocated into the nucleus binds p73 to induce pro-apoptotic gene expression. Active Itch ubiquitinates and promotes proteosomal degradation of tBid. Itch also poly-ubiquitinates LATS1 and p73 and targets these proteins for degradation. Gray arrows indicate catalysis, black arrows indicate transformation and red blunt arrows indicate inhibition.