Scribble sub-cellular localization modulates recruitment of YES1 to regulate YAP1 phosphorylation
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Updated: Nov 12, 2025

All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System
Published on: December 20, 2021
Dongyu Zhao1, Zhangyuan Yin2, Matthew B Soellner3
1Program in Chemical Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract:
The multi-domain scaffolding protein Scribble (Scrib) regulates cell polarity and growth signaling at cell-cell junctions. In epithelial cancers, Scrib mislocalization and overexpression paradoxically transform Scrib from a basolateral tumor suppressor to a cytosolic driver of tumorigenicity. To address the function of Scrib (mis)localization, a Scrib-HaloTag fusion was genome engineered in polarized epithelial cells. Expression of the epithelial to mesenchymal transcription factor Snail displaced Scrib-HaloTag from cell junctions, mirroring the mislocalization observed in cancers. Interestingly, Snail expression promotes Yes-associated protein-1 (YAP1) nuclear localization independent of hippo pathway-regulated YAP-S127 phosphorylation. Furthermore, Scrib HaloPROTAC degradation attenuates YAP1-Y357 phosphorylation. Halo-ligand affinity purification mass spectrometry analysis identified the Src family kinase YES1 as a mislocalized Scrib interaction partner, preferentially recruiting the kinase active and open global conformation (αC helix in). Altogether, mislocalized Scrib enhances YAP1 phosphorylation by scaffolding active YES1.
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