# O-GlcNAcylation of the tumor suppressor LATS1 drives mitotic progression via PLK1

## TL;DR

This study shows how O-GlcNAcylation of LATS1 affects mitotic progression and cell growth through interactions with PLK1 and the Hippo pathway.

## Contribution

The study reveals a novel mechanism where O-GlcNAcylation of LATS1 regulates mitotic progression via PLK1.

## Key findings

- LATS1 is O-GlcNAcylated at S479/S482/T484/T485 by OGT, reducing its stability and downstream phosphorylation.
- O-GlcNAcylation of LATS1 enhances PLK1 activity and mitotic progression by decreasing MYPT1 phosphorylation.
- In Drosophila, O-GlcNAcylated LATS1 promotes increased wing size, linking glucose levels to cell proliferation.

## 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.