Mesenchymal Transglutaminase 2 Activates Epithelial ADAM17: Link to G-Protein-Coupled Receptor 56 (ADGRG1)...

Area of Science:

• Cell biology
• Biochemistry
• Dermatology

Background:

• Mesenchymal-matrix-associated transglutaminase 2 (TG2) plays a role in keratinocyte re-epithelialization during wound healing.
• TG2 influences keratinocyte migration through the activation of disintegrin and metalloproteinase 17 (ADAM17).

Purpose of the Study:

• To elucidate the role of TG2 in keratinocyte re-epithelialization.
• To investigate the interaction between TG2 and the adhesion G-protein-coupled receptor GPR56 in keratinocyte migration.

Main Methods:

• Development of a wound healing model.
• Assessment of keratinocyte migration in TG2-positive and TG2 null conditions.
• Luciferase reporter assays to measure ADAM17 activation and GPR56 activation by TG2.
• Analysis of TG2 and GPR56 endocytosis and binding kinetics.

Main Results:

• TG2 activation of ADAM17 leads to EGFR transactivation and keratinocyte migration on TG2-positive extracellular matrix (ECM).
• Keratinocyte migration is impaired under TG2 null conditions.
• TG2 activates GPR56, a proposed TG2 receptor, in a manner dependent on the N-terminal GPR56 domain and TG2 β-barrel domains.
• The TG2-GPR56 interaction involves RhoA and ADAM17 activation and leads to EGFR transactivation.
• TG2 binds to the N-terminal GPR56 domain, with only the calcium-enabled TG2 conformation showing association.

Conclusions:

• TG2 and GPR56 form a ligand-receptor pair that drives keratinocyte migration via RhoA and EGFR transactivation.
• This interaction is critical for effective re-epithelialization in wound healing.
• Targeting the TG2-GPR56 pathway may offer therapeutic strategies for enhancing skin repair.