Image of the histoblasts, the cells that form the abdomen of the adult fruit fly.

Nic Tapon : Regulation of Hippo signalling by the Salt-inducible kinases

Introduction

In order to shed light on Hpo pathway upstream signalling, we have performed a genome-wide RNAi screen in cell culture in collaboration with the High-Throughput Screening Facility at the Crick headed by Mike Howell, and Moritz Rossner's lab at the Max Planck Institute in Göttingen.

The screen is based on the Split-TEV (Tobacco Etch Virus) technology developed in the Rossner lab, which allows us to detect the phospho-dependent interaction between Yki and 14-3-3. Using this approach, we identified the Salt-inducible kinases (Sik) as regulators of Hpo signalling. Activated Sik2 and 3 kinases increase Yki target expression and promote tissue overgrowth through inhibitory phosphorylation of Sav at Serine 413.

Siks play a major role in inhibiting gluconeogenesis in the liver in response to high glucose levels through inhibitory phosphorylation of the transcriptional co-activator CRTC2 (CREB-regulated transcription coactivator 2)/TORC2, and activatory phosphorylation of the Histone Deacetylase HDAC4, a function which appears to be conserved in Drosophila.

The Siks are under hormonal control by Insulin receptor (InR) signalling and Glucagon (Adipokinetic Hormone (AKH) in flies). InR activates Akt, which phosphorylates and activates Sik2/3. Glucagon signals through a G-protein coupled receptor (GPCR), inducing PKA activation, which phosphorylates and inhibits Sik2/3.

Under fasting conditions in flies, low Insulin and high AKH activity combine to inhibit Sik3, thereby promoting gluconeogenesis and inducing mobilisation of Fat Body (FB - the fly liver equivalent) lipid stores to restore circulating glucose levels and energy homeostasis. Thus, we hypothesise that Sik kinases may provide a nutritional/metabolic input to Hpo signalling, ensuring that Yki drives tissue growth only under favourable conditions.