MET receptor activation mechanisms by HGF/SF: New insights about N and K1
domains contribution.
Claire Simonneau*,a Berenice Leclercq,a Alexandra Mougel,a Eric Adriaenssens,a
Charlotte Paquet,b Laurent Raibaut,a Nathalie Ollivier,a Hervé Drobecq,a Julien
Marcoux,c Sarah Cianferani,c David Tulasne,a Hugo de Jonge,d Oleg Melnyka and
Jérôme Vicogne.a
a
UMR CNRS 8161 CNRS, Université de Lille, Institut Pasteur de Lille, 1 rue du Pr
Calmette, 59021 Lille Cedex, France.
b
SIRIC ONCOLille, 6 rue du Pr. Laguesse, 59037 Lille Cedex, France.
c
UMR 7178 CNRS. Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO),
IPHC-DSA, Université de Strasbourg, 25 rue Becquerel, 67087 Strasbourg, France.
d
Division of Immunology and General Pathology, Department of Molecular Medicine,
University of Pavia, 9 via A Ferrata, 27100 Pavia, Italy.
Hepatocyte Growth Factor/Scatter Factor (HGF/SF) and its receptor tyrosine
kinase MET play an essential role in embryogenesis and tissue regeneration, but are
also strongly involved in tumor progression and invasion mechanisms. Although
numerous biological and structural approaches have been focused on the molecular
processes leading to MET activation by HGF/SF, the HGF/SF-MET interaction
framework remains only partially understood due to the complexity of the multivalent
ligand-receptor binding events.
NK1, a naturally occurring splice variant of HGF/SF, comprising the N domain
(N-terminal part) and the first kringle domain (K1) of HGF/SF, exhibits a partial
agonistic activity towards MET. Indeed, in the presence of heparan sulfates (HS),
NK1 self-associates into a “head-to-tail” dimer which is considered as the minimal
structural module able to trigger MET dimerization and activation. Nevertheless, the
individual role of N and K1 domains in the dimerization/activation of MET remains
elusive.
Stimulated by the notion that monomeric N and K1 domains are not suitable
for studying the functioning of HGF/SF-MET, we produced biotinylated analogs of the
N and K1 domains (NB and K1B) by total chemical synthesis.1,2 We engineered
semisynthetic constructs by combining NB and K1B with streptavidin (S) in order to
determine the biological properties of these new multivalent architectures.
In vitro, as observed with HGF/SF or NK1, we show that the K1B/S complex
is able to fully activate MET signaling cascades to promote scattering,
morphogenesis and survival phenotypes in various cell types. Even more, the K1B/S
complex stimulates angiogenesis in vivo and, when injected systemically, triggers
MET signaling in the liver. The use of this K1B/S complex allows us to demonstrate
that two K1 domains, correctly assembled and oriented, constitute the minimal unit
for sufficient MET activation.3 In contrast, in vitro data have demonstrated that NB/S
complex does not bind directly MET as previously thought, but rather, uses HS as a
molecular bridge.
We envision these structural configurations serving as a template for the
rational design of both potent MET agonists and antagonists.
1.
2.
3.
L. Raibaut, J. Vicogne, B. Leclercq, H. Drobecq, R. Desmet, and O. Melnyk.
Bioorg. Med. Chem., 2013, 21, 3486–3494.
N. Ollivier, J. Vicogne, A. Vallin, H. Drobecq, R. Desmet, O. El-Mahdi, B.
Leclercq, G. Goormachtigh, V. Fafeur and O. Melnyk. Angew. Chem., Int. Ed.,
2012, 51, 209-213.
C. Simonneau, B. Leclercq, A. Mougel, E. Adriaenssens, C. Paquet, L.
Raibaut, N. Ollivier, H. Drobecq, J. Marcoux, S. Cianferani, D. Tulasne, H. de
Jonge, O. Melnyk and J. Vicogne. Chem. Sci., 2015, 6, 2110 - 2121.