The Hippo signaling pathway represents a critical regulatory mechanism governing organ size control, tissue homeostasis, and tumor suppression through modulation of the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). This review focuses on recent structural biology advances in understanding the molecular architecture and regulatory mechanisms of the Hippo pathway. We examine the core signaling complexes, mammalian sterile 20-like kinases 1 and 2 (MST1/2)-Salvador ortholog 1 (SAV1) and large tumor suppressor 1/2 (LATS1/2)-Mps One Binder (MOB1), revealing their intricate assembly mechanisms and activation dynamics. The review highlights the striatin-interacting phosphatase and kinase (STRIPAK) complex as a pivotal negative regulator through its unique PP2A-striatin core architecture. We further explore upstream regulatory proteins including NF2/Merlin and angiomotin family proteins, highlighting angiomotin-induced conformational changes and membrane-associated spatial organization that orchestrate pathway activation. Importantly, disease-associated mutations cluster at critical structural interfaces, providing mechanistic insights into pathological Hippo pathway dysregulation. These structural studies not only advance our fundamental understanding of signal transduction mechanisms but also provide a foundation for exploiting the Hippo pathway in regenerative medicine and cancer therapy.
Lu et al. (Mon,) studied this question.