Signalisation cellulaire et neurofibromatose

Neurofibromatosis type 1 :

Neurofibromatosis type 1 (NF1) is a very common genetic disease. NF1 phenotype is highly variable, however the hallmark of NF1 is the development of nerve tumors with an increased risk of malignancies, and neurological disorders. Currently, NF1 treatments remain poorly efficient, and identifying new therapeutic targets to treat this disease is a challenge for the forthcoming years.

NF1 is due to mutations within the NF1 tumor suppressor gene, which encodes for neurofibromin, Nf1, a huge protein. We performed a two-hybrid screening and identified new partners of Nf1. We decided to focus on three of them, LINGO-1, LARP6, and LIMK2. We are also working on 5-HT6 receptor, which was identified as a new partner of Nf1 by a proteomic approach developed by the team of P.Marin (IGF, Montpellier). 5-HT6 receptor is a serotonin receptor which is a promising target for the treatment of cognitive deficits. Its constitutive activity on cAMP is regulated by Nf1. LINGO-1 plays a key role in different processes of the central nervous system (neuronal growth and survival, myelinisation), we are studying its functional interaction with Nf1. LARP6 regulates type I collagen mRNA translation, we showed that Nf1 disturbs the interaction between LARP6 and type I collagen mRNA. LIMK2 is a kinase involved in cytoskeleton remodeling, especially actin cytoskeleton via Rho/ROCK/LIMK2/cofilin pathway.

We showed that Nf1 negatively regulates this pathway by preventing LIMK2 activation by ROCK. We are also working on the three human isoforms of LIMK2, and we showed that one of them is involved in mental deficiency.
On another hand, we are part of a collaborative network with bioanalysts and chemists, to develop new inhibitors of LIM kinases (LIMK1 and LIMK2). Besides the connexion between NF1 and LIMK2, LIM kinases are misregulated in many cancers. They constitute new attractive therapeutic targets. In a previous similar collaborative project, we have developped new inhibitors of PI3K and mTOR, the most efficient molecules are currently under preclinical trial.

Collaborations sur la Neurofibromatose de type 1 :

CBM, Orléans, Equipe « Aspects moléculaires du vivant »
- Groupe thématique : « Réparation de l’ADN : structure, fonction et dynamique » Dr. F. Culard
- Groupe thématique : « Spectrométrie de masse fonctionnelle des métastases » Dr. M. Cadene
ICOA, Université d’Orléans :
- « Synthèse hétérocyclique et chimie thérapeutique » Pr. S. Routier, Dr. K. Plé, Dr. F. Buron
- « Bioinformatique structurale et chemoinformatique » Pr. P. Bonnet, Dr. S. Aci
- « Extraction, analyse de molécules bioactives » Dr. R. Néhmé
Chimie Organique et Chimie thérapeutique, Université de Nantes :
- Pr. J.M. Robert
IMVC, Université de Rennes 1 :
- Pr. JP Bazureau
Station Biologique de Roscoff :
- « Plateforme de criblage KISSF » Dr. S. Ruchaud
INSERM U1069, Faculté de Médecine Tours :
- Dr. M.L Jourdan
INSERM U930, Faculté de Médecine Tours :
- « Neurogénétique et neurométabolomique » Pr. C. Andrès, Dr. P. Vourc’h
IGF, Département Neurosciences, Montpellier :
- Dr. P. Marin
Division of Cancer and Genetics, Cardiff University, Grand Bretagne :
- Pr. M. Upadhyaya
KeyObs, Orléans :
- F. Trovero

C-VALO/FEDER*, Projet de maturation PELICAN : Validation préclinique des inhibiteurs de LIMK, kinases impliquées dans la dynamique du cytosquelette dans les glioblastomes.
Investigateurs principaux : Dr H. Bénédetti (CBM) et Pr. S. Routier (ICOA).

FEDER*, Projet NEUROSKIN : Nouvelle approche thérapeutique innovante à base d’ARN messager (ARNm) pour soigner la Neurofibromatose de type I.
Investigateurs principaux : Dr H. Bénédetti (CBM) et Pr. C. Pichon (CBM)

CNRS Innovation, Projet Pré-maturation : Validation préclinique des inhibiteurs de LIMK dans le cancer.
Investigateurs principaux : Dr H. Bénédetti (CBM) et Pr.S. Routier (ICOA) en collaboration avec le Dr F. Verrechia, Université de Nantes.

*Ces projets ont été financés par l'Union Européenne. L'Europe s'engage en région Centre-Val de Loire avec le Fonds européen de développement régional.

Principales publications :

• Tastet J., Cuberos H., Vallée B., Toutain A., Raynaud M., Marouillat S., Thépault R.-A., Laumonnier F., Bonnet-Brilhault F., Vourc’h P., Andres C. R. and Bénédetti H. (2019) LIMK2-1 is a Hominidae-Specific Isoform of LIMK2 Expressed in Central Nervous System and Associated with Intellectual Disability. Neuroscience, (2019) 399, 199-210.
• Vallée B., Cuberos H., Doudeau M., Godin F., Gosset D., Vourc’h P., Andres C. R. and Bénédetti H. (2018) IMK2-1, a new isoform of Human-LIMK2, regulates actin cytoskeleton remodeling via a different signaling pathway than its two homologs, LIMK2a/2b.Biochemical Journal (2018) 475 () 3745-3761.
• Deraredj Nadim W., Chaumont-Dubel S., Madouri F., Cobret L., De Tauzia M.-L., Zajdel P., Bénédetti H., Marin P. and Morisset-Lopez S. (2016) A Physical Interaction between Neurofibromin and Serotonin 5-HT6 Receptor Promotes Receptor Constitutive Activity., Proc Natl Acad Sci U S A  113(43) 12310-12315 -doi: 10.1073/pnas.1600914113
• Saurat T., Buron F., Rodriguès N., de Tauzia M.-L., Colliandre L., Bourg S., Bonnet P., Guillaumet G., Akssira M., Corlu A., Guillouzo C., Berthier P., Rio P., Jourdan ML., Bénédetti H. and Routier S. (2014) Design, Synthesis and Biological Activity of Pyridopyrimidine Scaffolds as Novel PI3K/ mTOR Dual Inhibitors. J. Med. Chem., 57, 613-631.
• Vallée B., Doudeau M., Godin F., Gombault A., Tchalikian A., de Tauzia M.-L., and Bénédetti H. (2012) Nf1 RasGAP Inhibition of LIMK2 Mediates a New Cross- Talk between Ras and Rho Pathways. PLOS One, 7, e47283.
• Godin F., Villette S., Vallée B., Doudeau M., Morisset-Lopez S., Ardourel M., Hevor T., Pichon C. and Bénédetti H. (2012) A fraction of neurofibromin interacts with PML bodies in the nucleus of the CCF astrocytoma cell line. BBRC, 418, 689-694.