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The adhesion GPCR ADGRL2 engages Gα13 to enable epidermal differentiation
Xue Yang1,2, Feng He3, Vanessa Lopez-Pajares1
1Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305.
Summary
Researchers discovered a new signaling pathway essential for skin cell development. The adhesion GPCR ADGRL2 (latrophilin 2) activates Gα13, which is crucial for epidermal differentiation and maintaining skin homeostasis.
Area of Science:
- Cell biology
- Dermatology
- Molecular signaling
Background:
- Homeostasis depends on cell membrane receptors and signaling networks.
- G-protein-coupled receptors (GPCRs) are the largest transmembrane receptor family, but their epidermal roles are unclear.
Purpose of the Study:
- To investigate the roles of epidermal GPCRs in skin homeostasis.
- To identify specific GPCRs and their downstream signaling partners involved in epidermal differentiation.
Main Methods:
- Utilized dual CRISPR-Flow and single-cell Perturb RNA-sequencing knockout screens for all epidermal GPCRs.
- Performed follow-up tissue knockouts and cryo-electron microscopy in lipid nanodiscs.
- Conducted in situ gene mutation studies to analyze specific protein-protein interactions.
Main Results:
- Identified adhesion GPCR ADGRL2 (latrophilin 2) as essential for epidermal differentiation.
- Demonstrated that ADGRL2 selectively activates the G protein Gα13.
- Revealed a specific interaction interface between ADGRL2 and Gα13 involving ADGRL2 intracellular loop 3 and Gα13's QQQ triplet sequence.
- Showed that Gα13 is also required for epidermal differentiation.
Conclusions:
- Established a novel ADGRL2-Gα13 signaling axis critical for epidermal differentiation.
- Highlighted the importance of specific molecular interfaces in GPCR-G protein activation for skin development.
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