Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer

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Abstract

Activation of heterotrimeric G-proteins (Gαβγ) by G-protein-coupled receptors (GPCRs) is a quintessential mechanism of cell signaling widely targeted by clinically approved drugs. However, it has become evident that heterotrimeric G-proteins can also be activated via GPCR-independent mechanisms that remain untapped as pharmacological targets. GIV/Girdin has emerged as a prototypical non-GPCR activator of G proteins that promotes cancer metastasis. Here, we introduce IGGi-11, a first-in-class small-molecule inhibitor of noncanonical activation of heterotrimeric G-protein signaling. IGGi-11 binding to G-protein α-subunits (Gαi) specifically disrupted their engagement with GIV/Girdin, thereby blocking noncanonical G-protein signaling in tumor cells and inhibiting proinvasive traits of metastatic cancer cells. In contrast, IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs. By revealing that small molecules can selectively disable noncanonical mechanisms of G-protein activation dysregulated in disease, these findings warrant the exploration of therapeutic modalities in G-protein signaling that go beyond targeting GPCRs.

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Zhao, J., DiGiacomo, V., Ferreras-Gutierrez, M., Dastjerdi, S., de Opakua, A. I., Park, J. C., … Garcia-Marcos, M. (2023). Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer. Proceedings of the National Academy of Sciences of the United States of America, 120(118). https://doi.org/10.1073/pnas.2213140120

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