Scribble sub-cellular localization modulates recruitment of YES1 to regulate YAP1 phosphorylation.

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.

• Authors: Dongyu Zhao, Zhangyuan Yin, Matthew B Soellner, Brent R Martin
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 28 Issue 8 Pg. 1235-1241.e5 (08 19 2021) ISSN: 2451-9448 [Electronic] United States
• PMID: 33730553 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• YAP-Signaling Proteins
• YAP1 protein, human
• Proto-Oncogene Proteins c-yes
• YES1 protein, human

Topics

• Animals
• Cells, Cultured
• Dogs
• Female
• Humans
• Male
• Phosphorylation
• Proto-Oncogene Proteins c-yes (genetics, metabolism)
• YAP-Signaling Proteins (genetics, metabolism)