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All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System
Published on: December 20, 2021
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Scribble sub-cellular localization modulates recruitment of YES1 to regulate YAP1 phosphorylation
Dongyu Zhao1, Zhangyuan Yin2, Matthew B Soellner3
1Program in Chemical Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Chemical Biology
|March 17, 2021
Summary
Mislocalized Scribble (Scrib) protein in cancer enhances tumor growth by scaffolding the active YES1 kinase, promoting YAP1 phosphorylation. This study reveals a novel mechanism linking Scrib mislocalization to tumorigenesis.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Oncology
Background:
- Scribble (Scrib) is a scaffolding protein crucial for cell polarity and growth signaling at cell junctions.
- In epithelial cancers, Scrib mislocalization and overexpression convert it from a tumor suppressor to a tumorigenicity driver.
Purpose of the Study:
- To investigate the functional consequences of Scrib (mis)localization in polarized epithelial cells.
- To elucidate the molecular mechanisms by which mislocalized Scrib contributes to cancer progression.
Main Methods:
- Genome engineering of a Scrib-HaloTag fusion protein in polarized epithelial cells.
- Induction of epithelial-mesenchymal transition using Snail expression.
- Halo-ligand affinity purification followed by mass spectrometry.
- Analysis of Yes-associated protein-1 (YAP1) phosphorylation and localization.
Main Results:
- Snail expression induced Scrib-HaloTag mislocalization from cell junctions, mimicking cancer-associated patterns.
- Snail promoted YAP1 nuclear localization independent of Hippo pathway signaling.
- Src family kinase YES1 was identified as a mislocalized Scrib interaction partner, preferentially in its active conformation.
- Mislocalized Scrib enhances YAP1 phosphorylation by scaffolding active YES1.
Conclusions:
- Scrib mislocalization, induced by factors like Snail, plays a critical role in promoting tumorigenicity.
- The interaction between mislocalized Scrib and active YES1 represents a novel mechanism driving YAP1 activation in cancer.
- Targeting the Scrib-YES1 interaction could offer new therapeutic strategies for epithelial cancers.
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