LATS kinase activity and tumor suppressor function are regulated by a second autophosphorylation site

Area of Science:

• Molecular Biology
• Cell Signaling
• Cancer Biology

Background:

• The Hippo signaling pathway is a critical regulator of organ size, controlling cell proliferation, differentiation, and apoptosis.
• LATS kinases (LATS1 and LATS2) are core components of the Hippo pathway, mediating its tumor-suppressive functions.
• LATS kinase activation involves phosphorylation events, including at the hydrophobic motif and activation loop, but precise regulatory mechanisms remain incompletely understood.

Purpose of the Study:

• To identify and characterize novel regulatory phosphorylation sites within LATS kinases.
• To elucidate the mechanistic role of these sites in LATS kinase activation and downstream signaling.
• To investigate the impact of LATS kinase regulation on YAP oncogenic activity within the Hippo pathway.

Main Methods:

• Site-directed mutagenesis was employed to substitute identified serine residues with alanine.
• Western blotting and phospho-specific antibodies were used to assess phosphorylation states.
• Analysis of YAP phosphorylation and oncogenic activity was performed in cellular models.

Main Results:

• A conserved autophosphorylation site, the canonical LATS1/2 substrate (CLS) site (Ser872 in LATS1, Ser835 in LATS2), was identified within a canonical HXRXXS motif.
• Phosphorylation at the CLS site is essential for the full activation of LATS kinases.
• Mutation of the CLS site significantly reduced YAP phosphorylation, leading to enhanced YAP oncogenic activity.

Conclusions:

• The CLS site represents a critical regulatory element for LATS kinase activation within the Hippo signaling pathway.
• Proper phosphorylation of the CLS site is necessary for LATS kinases to effectively inhibit YAP, a key oncogenic effector.
• These findings provide new mechanistic insights into Hippo pathway regulation and offer potential targets for cancer therapy.