OTUB2 promotes cancer metastasis via Hippo independent activation of YAP and TAZ, Zhang et al.

Upon activation of Hippo signaling, YAP and TAZ are phosphorylated by LATS1/2 and Casein 1δ/ε kinases, leading to poly-ubiquitination by SCF E3 ubiquitin ligase and proteasomal degradation. Although YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active, it is yet unknown whether YAP/TAZ can be stabilized via deubiquitination and thereby escape from the negative Hippo control.

Here, by a gain-of-function cancer metastasis screen we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on Lysine 233 and this SUMOylation enables it to bind YAP/TAZ. We also identified an as yet unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2.