WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy

Mol Cell. 2022 May 19;82(10):1850-1864.e7. doi: 10.1016/j.molcel.2022.03.027. Epub 2022 Apr 15.


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.

Keywords: Hippo; KIBRA; LATS1; LATS2; MST1; MST2; TAZ; WWC1; YAP; cancer.

MeSH terms

  • Carcinogenesis
  • Hippo Signaling Pathway
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction* / physiology
  • Tumor Suppressor Proteins / metabolism


  • Intracellular Signaling Peptides and Proteins
  • Tumor Suppressor Proteins
  • WWC1 protein, human
  • LATS1 protein, human
  • LATS2 protein, human
  • Protein Serine-Threonine Kinases