Targeting the Interaction between the SH3 Domain of Grb2 and Gab2.

Francesca Malagrinò,Lorenzo Visconti,Angelo Toto,Marianna Bufano,Romano Silvestri,Francesca Troilo,Antonio Coluccia,Francesca Cutruzzolà,Stefano Gianni,Alessio Paone,Michela Puxeddu,Giuseppe La Regina,Maria Chiara Magnifico

doi:10.3390/cells9112435

Francesca Malagrinò, Lorenzo Visconti + Show 11 more

Open Access

https://doi.org/10.3390/cells9112435

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Journal: Cells	Publication Date: Nov 7, 2020
Citations: 8	License type: CC BY 4.0

Affiliation: Istituto Pasteur, Sapienza University of Rome

Abstract

Gab2 is a scaffolding protein, overexpressed in many types of cancers, that plays a key role in the formation of signaling complexes involved in cellular proliferation, migration, and differentiation. The interaction between Gab2 and the C-terminal SH3 domain of the protein Grb2 is crucial for the activation of the proliferation-signaling pathway Ras/Erk, thus representing a potential pharmacological target. In this study, we identified, by virtual screening, seven potential inhibitor molecules that were experimentally tested through kinetic and equilibrium binding experiments. One compound showed a remarkable effect in lowering the affinity of the C-SH3 domain for Gab2. This inhibitory effect was subsequently validated in cellula by using lung cancer cell lines A549 and H1299. Our results are discussed under the light of previous works on the C-SH3:Gab2 interaction.

Highlights

IntroductionThe growth factor receptor-bound protein 2 (Grb2)-associated binding protein (Gab2) is a scaffolding protein that organizes several signaling pathways, acting as a platform for the assembly of complex interaction networks [1]
The growth factor receptor-bound protein 2 (Grb2)-associated binding protein (Gab2) is a scaffolding protein that organizes several signaling pathways, acting as a platform for the assembly of complex interaction networks [1].In response of specific stimuli from the membrane, Gab2 becomes activated – an event that triggers the interaction with diverse targets controlling critical cellular processes, such as proliferation, migration, and differentiation [2,3,4]
The obtained training set was docked by Plants to Grb2 C-SH3 domain

Summary

Introduction

The Grb2-associated binding protein (Gab2) is a scaffolding protein that organizes several signaling pathways, acting as a platform for the assembly of complex interaction networks [1]. In response of specific stimuli from the membrane, Gab becomes activated – an event that triggers the interaction with diverse targets controlling critical cellular processes, such as proliferation, migration, and differentiation [2,3,4]. While lacking any enzymatic functions, Gab works by transmitting and amplifying several signals downstream, in response to specific effectors. Gab was found overexpressed in breast [5], gastric [6] and lung [7] cancers. Gab knock out mice models, displaying a deficient allergic response and mast cells developments, are viable and fertile [9] and have proven to be a precious tool to pinpoint the role Its role is clearly established in hematological cancers, such as juvenile myelomonocytic leukemia [8], chronic myelogenous leukemia (CML) [9], acute leukemia [10] and acute lymphoblastic leukemia [11].

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