DC 5: Functional genomics of S6K1/2 specific substrates regulating cell size

Project part of Work Package 1

Objectives: Among the mTORC1 targets, S6 kinases 1 and 2 (S6K1 and S6K2) are exquisitely sensitive to nutrient availability and rapamycin inhibition. Of note, in vivo analysis of mutant mice reveals that S6K1 regulates cell size in a predominant way as compared to S6K2. Mutant animals also mimic a caloric restriction phenotype with decreased adiposity and increased lifespan. S6K1 may be therefore be key to the interconnection between cell size, and regenerative and aging responses. The PhD candidate will perform structure-function studies and phospho-proteomics to reveal:

selective targets of S6K1 vs. S6K2 mediating cell size control;
structural changes of key substrates upon phosphorylation;
suitable residues for the design of covalent S6K1/S6K2 inhibitors.

Molecular biology and genome editing tools will be used to produce mutant kinases and swap relevant domains in S6K1 and S6K2. Phosphoproteomics will broaden the list of S6K1 specific substrates that may be involved in cell size control. Protein modeling will clarify the kinase-substrate as well as inhibitor-kinase interactions in collaboration with the University of Tübingen (Prof. M. Gehringer). The molecular understanding of cell size control by mTOR/S6K1 should open new therapeutic perspectives for mTORopathy in which giant cells are a prominent pathological feature.

Expected Results: the PhD candidate will define the molecular landscape for cell size regulation by the mTOR/S6K pathway and open pharmacological strategies for specific targeting in mTORopathies.

Prospects of career development: Over the past 20 years, alumni from the Pende lab became group leaders/tenured researchers in Academia, University teaching professors, Project leaders in Pharma companies, Directors of Technological Facilities, Clinical Research Associates. The job opportunities for the Doctoral Candidates will be expanded by the multidisciplinary nature of the Research and Educational program, leading to potential recruitments in new fields (genetic tests, biomarkers analysis, cellular models, drug discovery and development) in both Academia and Industries.

Planned secondments: 3 months at Cell Signalling Technology for PTMScan Ser/Thr Kinase based phosphoproteomics to differentially identify S6K1 and S6K2 targets. 2 months at the University of Tübingen for evalulation of S6K1 versus S6K2 specific inhibitors. 2 months at University of Fribourg for S6K direct kinase assays.

Other information : Please note that in addition to the selection process conducted by the project consortium, the selected candidate will also be required to participate in a mandatory audition/interview with the doctoral school as part of the formal admission procedure