POPX2 is a novel LATS phosphatase that regulates the Hippo pathway

Area of Science:

• Cell biology
• Molecular oncology
• Signal transduction

Background:

• The Hippo pathway is crucial for regulating cell growth, survival, and differentiation.
• Dysregulation of the Hippo pathway, particularly its kinases, contributes to cancer development by promoting uncontrolled proliferation and survival.
• Negative regulators of Hippo pathway kinases are not well understood, representing a gap in knowledge.

Purpose of the Study:

• To identify novel negative regulators of the Hippo pathway kinases.
• To investigate the role of POPX2 phosphatase in Hippo pathway signaling.
• To determine the impact of POPX2 on cancer cell proliferation and growth.

Main Methods:

• Interactome screening to identify protein interactions with Hippo pathway kinases.
• Biochemical assays to assess phosphatase activity of POPX2 on LATS1.
• CRISPR-Cas9 gene editing to knock out POPX2 in MDA-MB-231 breast cancer cells.
• Analysis of YAP/TAZ nuclear translocation and target gene activation.

Main Results:

• POPX2 was identified as an interactor of Hippo pathway core kinases, including LATS1.
• POPX2 dephosphorylates LATS1 at Threonine-1079, leading to LATS1 inactivation.
• POPX2-mediated LATS1 inactivation results in YAP/TAZ dephosphorylation and nuclear translocation.
• POPX2 knockout in MDA-MB-231 cells reduced cell proliferation and anchorage-independent growth.

Conclusions:

• POPX2 acts as a negative regulator of the Hippo pathway by inactivating LATS1 kinase.
• POPX2 promotes cell proliferation and anchorage-independent growth through YAP/TAZ activation.
• POPX2 represents a potential therapeutic target in cancers driven by Hippo pathway dysregulation.