O -GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity

Significance The Hippo pathway plays a crucial role in maintaining tissue homeostasis. Generally, activated Hippo pathway effectors, YAP/TAZ, induce the transcription of their negative regulators, NF2 and LATS2, and this negative feedback loop maintains homeostasis of the Hippo pathway. However, YAP and TAZ are consistently hyperactivated in various cancer cells, enhancing tumor growth. Our study found that LATS2, a direct-inhibiting kinase of YAP/TAZ and a core component of the negative feedback loop in the Hippo pathway, is modified with O -GlcNAc. LATS2 O -GlcNAcylation inhibited its activity by interrupting the interaction with the MOB1 adaptor protein, thereby activating YAP and TAZ to promote cell proliferation. Thus, our study suggests that LATS2 O -GlcNAcylation is deeply involved in Hippo pathway dysregulation in cancer cells.