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Functional studies of tyrosine kinase fibroblast growth factor receptor (FGFR2), the adapter growth factor receptor-Bound protein 2 (Grb2) and tyrosine phosphatase SHP2


Cell signaling is regulated by enzymatic activities through reversible phosphorylation of amino acids side chains. In this way, Protein Tyrosine Kinases (PTKs) rule the regulation upon cell proliferation, cell-cycle, growth, migration and differentiation. In many cases kinases and phosphatases, like Shp2, work together. Once phosphorylated, PTKs do the recruitment of partners like Grb2, Shc, Ras, Sos, etc., to build up complexes known as ESCs (Early Signaling Complexes) that activate specific signaling pathways inside cells. FGFRs are key regulators of many of these signaling process which aberrances in its activity causes a variety of human cancer and developmental defects. Early studies have shown that Grb2 is an important regulator of FGFR2 and Shp2 by preventing respectively kinase and phosphatase activities before extra-cellular stimulus. Phosphorylation of Grb2 by FGFR2 abrogates its binding to the kinase, resulting in up-regulation of both FGFR2's kinase and Shp2's phosphatase activity. Dephosphorylation of Grb2 by Shp2 rescued the FGFR2-Grb2 complex. Grb2 is a constitutive controller over the mutually dependent activities of FGFR2 and Shp2 so it is a potential target to drugs development. Therefore, it is important to characterize the interactions basis among those proteins to understand the process that start cancer development. The objective is to create knowledge on both FGFR2 and Shp2 activities over Grb2 and on the mutual interaction between FGFR2 and Shp2. For this study recombinant proteins will be expressed and purified, so calorimetry and fluorescence techniques will be used to access kinetics parameters from FGFR2 and Shp2 activities over Grb2 and also possible conformational changes induced by the interaction among those proteins. These studies will contribute to establish basis to get more efficient drugs that will play as inhibitors on those signaling pathways that leads to cancer development. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SANCHES, KAROLINE; CARUSO, ICARO P.; ALMEIDA, FABIO C. L.; MELO, FERNANDO A. The dynamics of free and phosphopeptide-bound Grb2-SH2 reveals two dynamically independent subdomains and an encounter complex with fuzzy interactions. SCIENTIFIC REPORTS, v. 10, n. 1 AUG 3 2020. Web of Science Citations: 0.
SANCHES, KAROLINE; RODRIGUES DIAS, RAPHAEL VINICIUS; DA SILVA, PAULO HENRIQUE; FOSSEY, MARCELO ANDRES; CARUSO, ICARO PUTINHON; DE SOUZA, FATIMA PEREIRA; DE OLIVEIRA, LEANDRO CRISTANTE; DE MELO, FERNANDO ALVES. Grb2 dimer interacts with Coumarin through SH2 domains: A combined experimental and molecular modeling study. HELIYON, v. 5, n. 11 NOV 2019. Web of Science Citations: 0.
SANCHES, KAROLINE; CARUSO, ICARO P.; ALMEIDA, FABIO C. L.; MELO, FERNANDO A. NMR assignment of free H-1, N-15 and C-13-Grb2-SH2 domain. BIOMOLECULAR NMR ASSIGNMENTS, v. 13, n. 2, p. 295-298, OCT 2019. Web of Science Citations: 0.

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