Hijacking the interaction between Gab2 and PI3K proteins
Gab2, a key member of the Gab family of proteins, is a scaffolding protein involved in the amplification and integration of signal transduction. For this reason Gab2 is implicated in several cellular functions such as cell proliferation, survival, migration and differentiation. Gab 2 has been associated to several cancers of both solid and haematological origin. In particular Gab2 is overexpressed in breast, gastric, and lung cancers.
From a structural point of view, Gab2 is composed by 676 amino acids organized in a folded N-terminal PH domain (of about 120 amino acids) and a disordered C-terminal region. Despite this large portion of Gab2 is disordered, it is nevertheless functional and extremely important, as it mediates directly the interaction with the many cytoplasmic partners, containing SH2 or SH3 domains. Upon activation of some receptor tyrosine kinases (RTKs), the scaffold Gab2 becomes tyrosyl phosphorylated and interacts with SH2 domain containing signal relay molecules, including the p85 subunit of phosphoinositide-3-kinase (PI3K).
PI3K protein is an important physiological partner of Gab2 and it is composed by a regulatory subunit called p85 and a catalytic subunit called p110, that can catalyze the formation of the lipid membrane PIP3. Gab2 can directly interact with PIP3, remaining anchored to the membrane and allowing the correct transduction of the signal.
This project is based on the hypothesis that an effective chemotherapeutic strategy would be that of interfering with the Gab2/PI3K interaction. Hence, we plan to address the mechanism of interaction between the disordered regions of Gab2 and the SH2 domains of PI3K, with the final goal of designing specific inhibitors to hijack such interactions.