Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators

Garcia‐Marcos, Mikel

doi:10.7554/elife.65620

Cited by 16 publications

(11 citation statements)

References 74 publications

(154 reference statements)

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“…4 A ). The lack of complete Akt inhibition is consistent with the known existence of GIV-independent mechanisms utilized by EGFR to activate PI3K–Akt signaling ( 37 ). In fact, the extent of IGGi-11me-mediated inhibition of Akt was similar to that observed upon depletion of GIV in these cell lines ( Fig.…”

Section: Resultssupporting

confidence: 79%

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

Zhao

DiGiacomo

Ferreras-Gutiérrez

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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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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Section: Resultssupporting

confidence: 79%

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

Zhao

DiGiacomo

Ferreras-Gutiérrez

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous results in vitro and in cell culture are compatible with this model. The GBA protein GIRDIN/GIV dissociates Gα i βγ more effectively than RGS12 ( 66 ), but the RGS12 GoLoco motif has a higher affinity for GNAI3 than GIRDIN GBA motif ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

2022

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Inhibitory G proteins (GNAI/Gα i ) bind to the scaffold G protein signaling modulator 2 (GPSM2) to form a conserved polarity complex that regulates cytoskeleton organization. GPSM2 keeps GNAI in a guanosine diphosphate (GDP)-bound state, but how GPSM2-GNAI is generated or relates to heterotrimeric G protein signaling remains unclear. We find that RGS12, a GTPase-activating protein (GAP), is required to polarize GPSM2-GNAI at the hair cell apical membrane and to organize mechanosensory stereocilia in rows of graded heights. Accordingly, RGS12 and the guanine nucleotide exchange factor (GEF) DAPLE are asymmetrically co-enriched at the hair cell apical junction, and Rgs12 mouse mutants are deaf. GPSM2 and RGS12 share GoLoco motifs that stabilize GNAI(GDP), and GPSM2 outcompetes RGS12 to bind GNAI. Our results suggest that polarized GEF/GAP junctional activity might dissociate heterotrimeric G proteins, generating free GNAI(GDP) for GPSM2 at the adjacent apical membrane. GPSM2-GNAI(GDP), in turn, imparts asymmetry to the forming stereocilia to enable sensory function in hair cells.

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“…4C), indicating that it does not interfere with GPCR-mediated G-protein signaling. In contrast, pertussis toxin (PTX), which precludes Gαi activation by GPCRs but not by GIV (37), efficiently blocked activation of Akt in response to SDF-1α but not to EGF (Fig. 4C).…”

Section: Iggi-11me Does Not Affect Giv-independent G-protein Cell Sig...mentioning

confidence: 99%

Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression

Zhao

DiGiacomo

Ferreras-Gutiérrez

et al. 2023

Preprint

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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 non-canonical activation of heterotrimeric G-protein signaling. IGGi-11 binding to G-protein α-subunits (Gαi) specifically disrupted their engagement with GIV/Girdin, thereby blocking non-canonical G-protein signaling in tumor cells, and inhibiting pro-invasive traits of metastatic cancer cells in vitro and in mice. In contrast, IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs. By revealing that small molecules can selectively disable non-canonical 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.

show abstract

Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators

Cited by 16 publications

References 74 publications

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

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

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression

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