Targeting the oncogenic signalling adaptor proteins CRKL, GAB2 and FRS2
| Componente | Categoria |
|---|---|
| Francesca Cutruzzola' | Componenti strutturati del gruppo di ricerca / Structured participants in the research project |
| Angelo Toto | Componenti strutturati del gruppo di ricerca / Structured participants in the research project |
| Maria Luisa Mangoni | Componenti strutturati del gruppo di ricerca / Structured participants in the research project |
| Livia Pagano | Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca / PhD/Assegnista/Specializzando member non structured of the research group |
| Valerio Consalvi | Componenti strutturati del gruppo di ricerca / Structured participants in the research project |
| Componente | Qualifica | Struttura | Categoria |
|---|---|---|---|
| Giovanna Boumis | Tecnico | Dip. Sc. Biochimiche | Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca / Other aggregate personnel Sapienza or other institution, holders of research scholarships |
| Francesca Malagrinò | Borsista AIRC | Dip. Sc. Biochimiche | Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca / Other aggregate personnel Sapienza or other institution, holders of research scholarships |
| Bruno Casciaro | Borsista Post Doc | Center for Life Nano Science, Istituto Italiano di Tecnologia, Roma | Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca / Other aggregate personnel Sapienza or other institution, holders of research scholarships |
CRKL, GAB2, and FRS2 are scaffolding adaptor proteins that are involved in various cellular processes, including cell proliferation, survival, migration, and differentiation. They are implicated in several malignancies, being recurrently amplified in several types of cancers and essential to cancer cell lines that harbor such amplification.
The function of the adaptor proteins CRKL, GAB2 and FRS2 is primarily mediated by their capability to assemble different proteins in specific complexes. This feature is provided by their modular structure containing SH2, SH3 and/or PTB domains, as well as proline-rich sequences (targeted by SH3 domains) or phospho-tyrosines (targeted by SH2 or PTB domains). Of additional interest, despite large portions of CRKL, GAB2 and FRS2 are disordered, these parts are nevertheless functional and extremely important as they mediate the interaction with their partners. Because of its highly dynamic properties, the structure of CRKL, GAB2 and FRS2 has, to date, escaped an experimental characterization. The project is therefore aimed at:
i) determining the structural features of the disordered regions of CRKL, GAB2 and FRS2 implicated in binding
ii) studying the structure of the complexes between the relevant domains of the physiological partners and the interacting regions of CRKL, GAB2 and FRS2
iii) characterizing the interactions between CRKL, GAB2 and FRS2 and their physiological partners
iv) pinpointing, by site-directed mutagenesis, the critical residues in the function of CRKL, GAB2 and FRS2
v) exploit structural and mechanistic knowledge to derive an in silico pharmacophore model, in order to find potential inhibitors of protein-protein interactions to be tested both in vitro and in cellula
As detailed in the Plan, uncoupling CRKL, GAB2 and FRS2 would result into the equivalent of having a cocktail of drugs targeting multiple enzymes, because their activation could be prevented simultaneously.