WWC proteins mediate LATS12 activation by Hippo kinases and imply a tumor suppression strategy

On April 15, 2022, Fa-Xing Yu, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, and hia team published a paper tittled “WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy” in Molecular Cell, which uncovered a molecular mechanism underlying LATS1/2 regulation and provided a strategy for treating diverse malignancies related to Hippo pathway dysregulation.

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YAP and TAZ (YAP/TAZ), two major effectors of the Hippo signaling pathway, are frequently activated in human cancers. The activity of YAP/TAZ is strictly repressed upon phosphorylation by LATS1/2 tumor suppressors. However, it is unclear how LATS1/2 are precisely regulated by upstream factors such as Hippo kinases MST1/2. Here, we show that WWC proteins (WWC1/2/3) directly interact with LATS1/2 and SAV1, and SAV1, in turn, brings in MST1/2 to phosphorylate and activate LATS1/2. Hence, WWC1/2/3 play an organizer role in a signaling module that mediates LATS1/2 activation by MST1/2. Moreover, we have defined a minimum protein interaction interface on WWC1/2/3 that is sufficient to activate LATS1/2 in a robust and specific manner. The corresponding minigene, dubbed as SuperHippo, can effectively suppress tumorigenesis in multiple tumor models. Our study has uncovered a molecular mechanism underlying LATS1/2 regulation and provides a strategy for treating diverse malignancies related to Hippo pathway dysregulation.

Hippo Signaling Pathway

The Hippo (or SWH) signaling pathway has been shown to be responsible for controlling organ growth and size by limiting cell proliferation and promoting apoptosis. At low cell densities, the co-activators YAP/TAZ induce the expression of transcription factors that lead the pathway toward cell proliferation. However at higher cell densities, membrane-bound regulators trigger YAP/TAZ phosphorylation, thereby preventing them from entering the nucleus to induce the pro-growth transcription factors. Mutations of the Hippo protein lead to overgrowth that is similar to the unchecked cell proliferation found in tumors.