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Scrib regulates HGF-mediated epithelial morphogenesis and is stabilized by Sgt1-HSP90
Dennis J Eastburn1, Mirjam M Zegers, Keith E Mostov
1Department of Anatomy, University of California, San Francisco, CA 94143, USA.
Journal of Cell Science
|May 25, 2012
Summary
Scribble (Scrib) protein stability is regulated by Sgt1 and HSP90 chaperones, crucial for epithelial cell migration and morphogenesis. This chaperone-mediated regulation impacts cell survival and protein trafficking pathways.
Area of Science:
- Cell Biology
- Molecular Biology
- Developmental Biology
Background:
- Scribble (Scrib) is an evolutionarily conserved protein implicated in cell survival, protein trafficking, adhesion, and migration.
- The precise molecular pathways governing Scrib's functions in mammalian cells remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying Scrib's role in epithelial morphogenesis.
- To investigate the association of Scrib with other cellular proteins and its regulation by chaperones.
Main Methods:
- Utilized a three-dimensional epithelial cell culture system to study Scrib function.
- Investigated protein-protein interactions using co-immunoprecipitation assays.
- Assessed the impact of inhibiting chaperones (Sgt1, HSP90) and key complex members (Scrib, βPix, PAK) on epithelial morphogenesis and tubulogenesis.
Main Results:
- Identified a novel association between the Scrib protein's leucine-rich repeat domain and the co-chaperone Sgt1.
- Demonstrated that Scrib, Sgt1, and HSP90 are essential for epithelial morphogenesis and tubulogenesis induced by hepatocyte growth factor (HGF).
- Showed that Sgt1 and HSP90 are required for maintaining Scrib protein levels and that their inhibition destabilizes the Scrib-βPix-PAK complex, blocking HGF-mediated morphogenesis.
Conclusions:
- Scrib functions as a client protein of the Sgt1-HSP90 chaperone complex, essential for regulating cell migration during morphogenesis.
- Chaperone-mediated regulation of polarity protein stability is a critical, yet underappreciated, mechanism governing dynamic cellular rearrangements in epithelial development.
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