O-GlcNAcylation: An Emerging Protein Modification Regulating the Hippo Pathway

Abstract

The balance between cellular proliferation and apoptosis and the regulation of cell differentiation must be established to maintain tissue homeostasis. These cellular responses involve the kinase cascade-mediated Hippo pathway as a crucial regulator. Hence, Hippo pathway dysregulation is implicated in diverse diseases, including cancer. O-GlcNAcylation is a non-canonical glycosylation that affects multiple signaling pathways through its interplay with phosphorylation in the nucleus and cytoplasm. An abnormal increase in the O-GlcNAcylation levels in various cancer cells is a potent factor in Hippo pathway dysregulation. Intriguingly, Hippo pathway dysregulation also disrupts O-GlcNAc homeostasis, leading to a persistent elevation of O-GlcNAcylation levels, which is potentially pathogenic in several diseases. Therefore, O-GlcNAcylation is gaining attention as a protein modification that regulates the Hippo pathway. This review presents a framework on how O-GlcNAcylation regulates the Hippo pathway and forms a self-perpetuating cycle with it. The pathological significance of this self-perpetuating cycle and clinical strategies for targeting O-GlcNAcylation that causes Hippo pathway dysregulation are also discussed.

MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression

“…The Hippo signaling pathway was first identified from Drosophila melanogaster by the genetic screening, which was an evolutionarily highly conserved kinase‐mediated signaling cascade to regulate cell proliferation and differentiation (Kim et al , 2022). The core components of classical Hippo pathway consist of the serine/threonine kinases mammalian Ste‐20‐like kinase 1/2 (MST1/2, Hippo in Drosophila) and large tumor suppressor 1/2 (LATS1/2), their scaffold proteins Salvador homolog 1 (SAV1) and Mps one binder 1 (MOB1), and the transcriptional co‐activators YAP/TAZ (Jin et al , 2022).…”

The role of O‐GlcNAcylation mediated by OGT during tooth development

“…In addition, the cusp and crown height ratio of the OGT‐inhibited teeth was significantly lower than that of control specimens (Supporting Information: Figure ). Other than these examined signaling molecules, OGT might regulate other tooth development‐related signaling pathways such as notch, TGF, and Hippo pathways (Kim et al, 2022). It would be interesting to find out whether these signaling molecules are regulated by OGT or not during tooth development in the near future.…”