| Autor: |
Jingyi Zhao, DiGiacomo, Vincent, Ferreras-Gutierrez, Mariola, Dastjerdi, Shiva, Ibáñez de Opakua, Alain, Jong-Chan Park, Luebbers, Alex, Qingyan Chen, Beeler, Aaron, Blanco, Francisco J., Garcia-Marcos, Mikel |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 5/2/2023, Vol. 120 Issue 18, p1-54, 54p |
| Abstrakt: |
Activation of heterotrimeric G-proteins (Gaß?) 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 a-subunits (Gai) 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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