Abstract
Initially discovered in Drosophila, the Hippo pathway is pivotal for tissue growth and organ homeostasis. It is regulated by both extrinsic and intrinsic signals and exerts its effect via a core kinase cascade, in which large tumor suppressor 1 and 2 (LATS1/2) plays a key role. LATS1 has also been shown to regulate mitotic progression by phosphorylating myosin phosphatase targeting subunit 1 (MYPT1) to counteract the activity of polo-like kinase 1 (PLK1), a mitotic master kinase. Herein, we demonstrate that the hexosamine biosynthetic pathway regulates the Hippo pathway via LATS1. We show that LATS1 interacts with the O-GlcNAc transferase (OGT) and is O-GlcNAcylated. Via electron transfer dissociation mass spectrometry, we mapped the O-GlcNAcylation sites to be S479/S482/T484/T485. O-GlcNAcylation attenuates LATS1 protein stability and downregulates the phosphorylation level of its downstream substrates, such as MYPT1. Subsequently, decreased MYPT1-pS473 levels enhance PLK1-pT210 levels and drive mitotic progression. Importantly, we demonstrate that in Drosophila O-GlcNAcylation of LATS1 promotes the wing size. Thus, this study suggests that O-GlcNAcylation links extrinsic glucose levels to LATS1 in the Hippo pathway and cell proliferation.
