Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent MET receptor agonist

Giovanni de Nola , Bérénice Leclercq (1) , Alexandra Mougel (1) , Solenne Taront (2) , Claire Simonneau , Federico Forneris (3) , Eric Adriaenssens (4, 5) , Hervé Drobecq (1) , Luisa Iamele , Laurent Dubuquoy (6) , Oleg Melnyk (1, 7) , Ermanno Gherardi (3) , Hugo de Jonge (8) , Jérôme Vicogne (1)

1 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
2 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
3 UNIPV - Università degli Studi di Pavia = University of Pavia
4 UNICANCER/Lille - Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille]
5 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
6 INFINITE (Ex-Liric) - Institute for Translational Research in Inflammation - U 1286
7 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
8 Science Faculty / Laboratory of Endocrinology and Metabolism

Hepatocyte growth factor/scatter factor (HGF/SF) and its cognate receptor MET play several essential roles in embryogenesis and regeneration in postnatal life of epithelial organs such as the liver, kidney, lung, and pancreas, prompting a strong interest in harnessing HGF/SF-MET signalling for regeneration of epithelial organs after acute or chronic damage. The limited stability and tissue diffusion of native HGF/SF, however, which reflect the tightly controlled, local mechanism of action of the morphogen, have led to a major search of HGF/SF mimics for therapy. In this work, we describe the rational design, production, and characterization of K1K1, a novel minimal MET agonist consisting of two copies of the kringle 1 domain of HGF/SF in tandem orientation. K1K1 is highly stable and displays biological activities equivalent or superior to native HGF/SF in a variety of in vitro assay systems and in a mouse model of liver disease. These data suggest that this engineered ligand may find wide applications in acute and chronic diseases of the liver and other epithelial organs dependent of MET activation.

Domaines: Embryologie et organogenèse; Biologie structurale [q-bio.BM]

Giovanni de Nola, Bérénice Leclercq, Alexandra Mougel, Solenne Taront, Claire Simonneau, et al.. Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent MET receptor agonist. Life Science Alliance, 2022, 5 (12), pp.e202201424. ⟨10.26508/lsa.202201424⟩. ⟨hal-03828723⟩