Hippo signaling pathway kinases (MST/LATS)

The Hippo-YAP pathway kinases, primarily comprising Mammalian Ste20-like kinases 1 and 2 (MST1/2) and Large tumor suppressor kinases 1 and 2 (LATS1/2), constitute a core tumor-suppressive signaling cascade that regulates organ size, cell proliferation, and apoptosis. In its active state, the MST1/2 kinases phosphorylate and activate LATS1/2, which in turn phosphorylate the transcriptional co-activators YAP and TAZ, leading to their cytoplasmic sequestration and subsequent degradation. Dysregulation of this pathway, often through loss-of-function mutations in upstream regulators like NF2 or the kinases themselves, leads to YAP/TAZ hyperactivation and is a hallmark of various cancers, including mesothelioma and hepatocellular carcinoma. Conversely, pharmacological inhibition of these kinases is being explored as a therapeutic strategy to promote tissue regeneration and wound healing by transiently activating YAP-driven proliferative programs. While most clinical-stage drugs target the downstream YAP-TEAD interaction, small-molecule inhibitors of MST and LATS are currently in preclinical development for regenerative medicine applications.

Other names

MST1/2LATS1/2Hippo kinasesCore Hippo kinasesMammalian Ste20-like kinasesLarge tumor suppressor kinasesSTK3/STK4Warts kinases

Inhibition of MST1/2 or LATS1/2 kinases prevents the phosphorylation of YAP and TAZ, facilitating their nuclear translocation and activation of gene transcription for tissue regeneration; activation of these kinases promotes YAP/TAZ degradation to suppress oncogenic growth.