Scribble sub-cellular localization modulates recruitment of YES1 to regulate YAP1 phosphorylation
| Autor: | Zhangyuan Yin, Brent R. Martin, Dongyu Zhao, Matthew B. Soellner |
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| Rok vydání: | 2021 |
| Předmět: |
Male
SCRIB Scaffold protein Clinical Biochemistry Biology 01 natural sciences Biochemistry Dogs Drug Discovery Cell polarity Animals Humans Src family kinase Phosphorylation Molecular Biology Transcription factor Cells Cultured Cellular localization Proto-Oncogene Proteins c-yes Pharmacology YAP1 010405 organic chemistry YAP-Signaling Proteins 0104 chemical sciences Cell biology Molecular Medicine Female |
| Zdroj: | Cell Chemical Biology. 28:1235-1241.e5 |
| ISSN: | 2451-9456 |
| DOI: | 10.1016/j.chembiol.2021.02.019 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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