Dr. Bin Zhao’s group published a research article on the Journal of Biological Chemistry online on November 28, 2017 with the title “Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway”. Dr. Bin Zhao is the corresponding author and a PhD candidate Chu Zhu is the first author.

The Hippo tumor suppressor pathway plays important roles in organ size control, tumorigenesis, tissue regeneration, and stem cell self-renewal. At the center stage of this pathway is the MST1/2-LATS1/2 kinase cascade. The activity of LATS1/2 is regulated by phosphorylation and ubiquitination. However, the mechanism that removes the ubiquitin modification from LATS2 and thereby stabilizes the protein is not well understood. In this study, using tandem affinity purification (TAP), Dr. Bin Zhao’s group found that a deubiquitylase USP9X specifically interacts with LATS2. USP9X knockout drastically diminished LATS2 protein levels. Further investigations demonstrated that USP9X deubiquitinates LATS2 and thus prevents LATS2 degradation by the proteasome. Moreover, in pancreatic cancer cells, USP9X loss activated YAP and enhanced the oncogenic potential of the cells. In addition, the tumorigenesis induced by the USP9X ablation depended not only on LATS2 repression, but also on YAP/TAZ activity. This study demonstrates that USP9X is a deubiquitylase of the Hippo pathway kinase LATS2 and that the Hippo pathway functions as a downstream signaling cascade that mediates USP9X’s tumor-suppressive activity.

A model illustrating the role of USP9X in the Hippo pathway.

Link:http://www.jbc.org/content/early/2017/11/28/jbc.RA117.000392.abstract?sid=33daef99-c18e-4450-a962-95b25cc7f694