Mesenchymal transglutaminase 2 activates epithelial ADAM17: link to G-protein coupled receptor 56 (ADGRG1) signalling

Bauer, Lea, Edwards, Jessica, Heil, Andreas ORCID: https://orcid.org/0000-0002-9536-5402, Dewitt, Sharon ORCID: https://orcid.org/0000-0001-8169-8241, Biebermann, Heike, Aeschlimann, Daniel ORCID: https://orcid.org/0000-0003-0930-7706 and Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924 2024. Mesenchymal transglutaminase 2 activates epithelial ADAM17: link to G-protein coupled receptor 56 (ADGRG1) signalling. International Journal of Molecular Sciences 25 (4) , 2329. 10.3390/ijms25042329

	PDF - Published Version Available under License Creative Commons Attribution. Download (4MB)
	PDF - Supplemental Material Available under License Creative Commons Attribution. Download (1MB)

Abstract

A wound healing model was developed to elucidate the role of mesenchymal-matrix-associated transglutaminase 2 (TG2) in keratinocyte re-epithelialisation. TG2 drives keratinocyte migratory responses by activation of disintegrin and metalloproteinase 17 (ADAM17). We demonstrate that epidermal growth factor (EGF) receptor ligand shedding leads to EGFR-transactivation and subsequent rapid keratinocyte migration on TG2-positive ECM. In contrast, keratinocyte migration was impaired in TG2 null conditions. We show that keratinocytes express the adhesion G-protein-coupled receptor, ADGRG1 (GPR56), which has been proposed as a TG2 receptor. Using ADAM17 activation as a readout and luciferase reporter assays, we demonstrate that TG2 activates GPR56. GPR56 activation by TG2 reached the same level as observed with an agonistic N-GPR56 antibody. The N-terminal GPR56 domain is required for TG2-regulated signalling response, as the constitutively active C-GPR56 receptor was not activated by TG2. Signalling required the C-terminal TG2 β-barrel domains and involved RhoA-associated protein kinase (ROCK) and ADAM17 activation, which was blocked by specific inhibitors. Cell surface binding of TG2 to the N-terminal GPR56 domain is rapid and is associated with TG2 and GPR56 endocytosis. TG2 and GPR56 represent a ligand receptor pair causing RhoA and EGFR transactivation. Furthermore, we determined a binding constant for the interaction of human TG2 with N-GPR56 and show for the first time that only the calcium-enabled “open” TG2 conformation associates with N-GPR56.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Publisher:	MDPI
ISSN:	1661-6596
Date of First Compliant Deposit:	14 February 2024
Date of Acceptance:	7 February 2024
Last Modified:	20 Feb 2024 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/166304

Actions (repository staff only)

Edit Item