Functional proteomics of CXCR4 and CXCR7-associated signalling networks

Early stage researcher 12 (ESR12) project – Amos Fumagalli
Supervision: Dr P Marin, Dr M Séveno, Dr S Chaumont-Dubel, Dr S Urbach
Host: CNRS (FR) – Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U1191,

Université de Montpellier

I- Project proposal:

1. Identify intracellular partners (GIPs) of CXCR4 and CXCR7 using an AP-MS proteomics strategy.

2. Determine functional consequences of CXCR4 and CXCR7 association with identified GIPs.

3. Decipher the phosphoproteomes resulting from CXCR4 and CXCR7 activation by different modulators.

Proteins interacting with epitope-tagged versions of CXCR4 and CXCR7 receptors will be purified by immunoprecipitation and affinity-purified proteins will be systematically identified by Nano-flow liquid chromatography coupled with Fourier transform tandem mass spectrometry (Nano-LC-FT-MS/MS). The influence of identified partners on receptor-operated signal transduction will be investigated by overexpressing or silencing expression of candidate partners and using tools and/or biosensors developed in this consortium. Phosphoproteomes generated upon receptor activation by different modulators will be deciphered by combining Stable Isotope Labelling by Amino acids in Cultured cells (SILAC) and a double-phosphopeptide enrichment procedure consisting of Hydrophilic Interaction Liquid Chromatography (HILIC) followed by Immobilized Metal Affinity Chromatography (IMAC). Planned secondments: Actelion (CH), Vivia Biosystems (ES)


II- Requirement candidate:

Required diploma: MSc degree in molecular/biomedical Life Sciences, Pharmaceutical Sciences or related Life Science degree.

Required expertise: cell culture, cell-based assays, biochemistry, molecular biology. Recommended expertise: Basic knowledge in mass spectrometry, proteomics, protein databases, bioinformatics and statistics.

Key publications:
1. Duhr, F., Deleris, P., Raynaud, F., Seveno, M., Morisset-Lopez, S., Mannoury la Cour, C., Millan, M. J., Bockaert, J., Marin, P. & Chaumont-Dubel, S. (2014) Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth Nat Chem Biol 10, 590-597. News and Views: Seo and Tsai. Neuronal differentiation: 5-HT6R can do it alone. Nat Chem Biol 10, 590-597.

2. Karaki, S., Becamel, C., Murat, S., Mannoury la Cour, C., Millan, M. J., Prezeau, L., Bockaert, J., Marin, P. & Vandermoere, F. (2014) Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists. Mol Cell Proteomics 13, 1273-1285.

3. Meffre, J., Chaumont-Dubel, S., Mannoury la Cour, C., Loiseau, F., Watson, D. J., Dekeyne, A., Seveno, M., Rivet, J. M., Gaven, F., Deleris, P., Herve, D., Fone, K. C., Bockaert, J., Millan, M. J. & Marin, P. (2012) 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. EMBO Mol Med 4, 1043-1056.

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Vrije Universiteit Amsterdam