The adhesion GPCR ADGRL2 engages Gα13 to enable epidermal differentiation

Proc Natl Acad Sci U S A. 2025 Nov 25;122(47):e2508436122. doi: 10.1073/pnas.2508436122. Epub 2025 Nov 18.

Abstract

Homeostasis relies on signaling networks controlled by cell membrane receptors. Although G-protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors, their specific roles in the epidermis are not fully understood. Dual CRISPR-Flow and single cell Perturb RNA-sequencing knockout screens of all epidermal GPCRs were thus performed, uncovering an essential requirement for adhesion GPCR ADGRL2 (latrophilin 2) in epidermal differentiation. Among potential downstream guanine nucleotide-binding G proteins, ADGRL2 selectively activated Gα13. Follow-up tissue knockouts verified that Gα13 is also required for epidermal differentiation. A cryoelectron microscopy structure in lipid nanodiscs showed that ADGRL2 engages with Gα13 at multiple interfaces, including via an interaction between ADGRL2 intracellular loop 3 and a Gα13-specific QQQ glutamine triplet sequence in its GTPase domain. In situ gene mutation of this interface sequence impaired epidermal differentiation, highlighting an essential new role for an ADGRL2-Gα13 axis in epidermal differentiation.

Keywords: ADGRL2; G proteins; adhesion GPCR; epidermal differentiation; structual biology.

MeSH terms

  • Animals
  • Cell Differentiation*
  • Epidermal Cells*
  • Epidermis* / metabolism
  • GTP-Binding Protein alpha Subunits, G12-G13* / chemistry
  • GTP-Binding Protein alpha Subunits, G12-G13* / genetics
  • GTP-Binding Protein alpha Subunits, G12-G13* / metabolism
  • Humans
  • Mice
  • Receptors, G-Protein-Coupled* / genetics
  • Receptors, G-Protein-Coupled* / metabolism
  • Receptors, Peptide* / genetics
  • Receptors, Peptide* / metabolism
  • Signal Transduction

Substances

  • Receptors, G-Protein-Coupled
  • GTP-Binding Protein alpha Subunits, G12-G13
  • Receptors, Peptide