NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway

Area of Science:

• Cell Biology
• Molecular Biology
• Developmental Biology

Background:

• The Hippo pathway is essential for organ size control and stem cell maintenance.
• While core kinase signaling is understood, modulators of Hippo pathway activity remain largely unknown.

Purpose of the Study:

• To identify novel regulatory components of the Hippo pathway.
• To elucidate the role of NEDD4 in Hippo pathway modulation and its impact on cell proliferation and apoptosis.

Main Methods:

• Identification of NEDD4 as a Hippo pathway regulator.
• Biochemical assays to demonstrate ubiquitylation and destabilization of WW45 and LATS kinase by NEDD4.
• Investigation of NEDD4's role in contact inhibition and intestinal stem cell renewal in Drosophila.

Main Results:

• NEDD4, a HECT-type E3 ubiquitin ligase, ubiquitylates and destabilizes WW45 and LATS kinase.
• MST1 kinase protects WW45 from NEDD4-mediated degradation.
• NEDD4 inactivation at high cell density is necessary for contact inhibition-induced Hippo pathway activation.
• NEDD4 promotes intestinal stem cell renewal in Drosophila by suppressing the Hippo pathway.

Conclusions:

• NEDD4 acts as a critical negative regulator of the Hippo pathway.
• NEDD4-mediated regulation of Hippo signaling is crucial for coordinating cell proliferation and apoptosis.
• This study uncovers a novel mechanism controlling organ size and stem cell homeostasis.