Atypical activation of the G protein Gαq by the oncogenic mutation Q209P

Maziarz, Marcin; Leyme, Anthony; Marivin, Arthur; Luebbers, Alex; Patel, Prachi P.; Chen, James Z.; Sprang, Stephen R.; Garcia‐Marcos, Mikel

doi:10.1074/jbc.ra118.005291

Cited by 33 publications

(48 citation statements)

References 79 publications

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“…In addition, we show that FR treatment is capable of producing similar results in metastatic UM cells containing GNAQ-Q209P or GNA11-Q209L mutations. Given the prevalence of Q209L and Q209P mutations in UM, it is worth noting that Ga q -Q209P has been shown to have altered binding to various effectors and Gbg compared with Ga q -Q209L, although it still effectively activates downstream signaling (50). FR treatment likely does not affect the growth of mutant BRAF cell lines such as OCM3 due to the lack of dependency on GNAQ/11 for cell growth (Figs.…”

Section: Discussionmentioning

confidence: 99%

Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma

Lapadula

Farías

Randolph

et al. 2019

Molecular Cancer Research

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Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gαq and Gα11, are observed in approximately 93% of all uveal melanomas. While therapeutic intervention of downstream Gαq/11 targets has been unsuccessful in treating uveal melanoma, using in vitro [35S]GTPγS binding and cell signaling assays we have found that the Gαq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gαq/11 signaling in uveal melanoma cells expressing either mutant Gαq or Gα11. Inhibition of oncogenic Gαq/11 by FR results in cell cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D‐cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gαq/11 mutants may be a potential means of treating uveal melanoma. Support or Funding Information Dr. Ralph and Marian Falk Medical Research Trust and NIH award F31 CA225064 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Section: Discussionmentioning

confidence: 99%

Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma

Lapadula

Farías

Randolph

et al. 2019

Molecular Cancer Research

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“…The G-proteins were His-tagged versions of Gαi3, Gαs, and Gαq purified from bacteria. For Gαq, we used a chimera containing partial sequences of Gαi (named here Gαq*) that can be expressed in bacteria and which has been previously validated to bind to a wide range of Gαq-specific partners (40). As observed with G-proteins from cell lysates, both GST-DAPLE and GST-GIV bound similarly to Gαi3, but only GST-DAPLE bound efficiently to Gαs and Gαq* (Fig.…”

Section: Daple Binds Efficiently Gαs and Gαq In Addition To Gαi3mentioning

confidence: 99%

“…Plasmid for the expression of His-Gαi3 (rat, pET28b-Gαi3) was described previously (19). Plasmids for the expression of His-Gαs (bovine, pHis6-Gαs) and His-Gαq* (mouse, pET28a-Gαq*) in bacteria were kindly provided by N. Artemyev (University of Iowa) and S. Sprang (University of Montana), respectively (40,57). Plasmids for expression of Gαq, Gβ1-His and Gγ2-His in Sf9 insect cells were described previously (46).…”

Section: Discusionmentioning

confidence: 99%

DAPLE protein inhibits nucleotide exchange on Gαs and Gαq via the same motif that activates Gαi

Marivin

Maziarz

Zhao

et al. 2020

Journal of Biological Chemistry

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Besides being regulated by G-protein–coupled receptors, the activity of heterotrimeric G proteins is modulated by many cytoplasmic proteins. GIV/Girdin and DAPLE (Dvl-associating protein with a high frequency of leucine) are the best-characterized members of a group of cytoplasmic regulators that contain a Gα-binding and -activating (GBA) motif and whose dysregulation underlies human diseases, including cancer and birth defects. GBA motif–containing proteins were originally reported to modulate G proteins by binding Gα subunits of the Gi/o family (Gαi) over other families (such as Gs, Gq/11, or G12/13), and promoting nucleotide exchange in vitro. However, some evidence suggests that this is not always the case, as phosphorylation of the GBA motif of GIV promotes its binding to Gαs and inhibits nucleotide exchange. The G-protein specificity of DAPLE and how it might affect nucleotide exchange on G proteins besides Gαi remain to be investigated. Here, we show that DAPLE's GBA motif, in addition to Gαi, binds efficiently to members of the Gs and Gq/11 families (Gαs and Gαq, respectively), but not of the G12/13 family (Gα12) in the absence of post-translational phosphorylation. We pinpointed Met-1669 as the residue in the GBA motif of DAPLE that diverges from that in GIV and enables better binding to Gαs and Gαq. Unlike the nucleotide-exchange acceleration observed for Gαi, DAPLE inhibited nucleotide exchange on Gαs and Gαq. These findings indicate that GBA motifs have versatility in their G-protein–modulating effect, i.e. they can bind to Gα subunits of different classes and either stimulate or inhibit nucleotide exchange depending on the G-protein subtype.

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“…Within the GNAQ and GNA11 genes, two particular codons are frequently mutated: arginine 183 and glutamine 209. Mutations at these two positions cause diminished GTPase function and so are linked to gain-of-signaling phenotypes (7,9,11,31,35,71). Interestingly, both are also considered oncogenic driver mutations in ocular (uveal) melanoma (UM), an aggressive malignancy of the adult eye (72)(73)(74)(75)(76).…”

Section: When the Balance Is Tipped Toward The On Statementioning

confidence: 99%

Heterotrimeric Gq proteins as therapeutic targets?

Kostenis¹,

Pfeil²,

Annala³

2020

Journal of Biological Chemistry

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Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein–coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the Gq family–specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of Gq oncoproteins, mutant Gq variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike Gq oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting Gq protein oncogenes as well as broaden our mechanistic understanding of Gq protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G(q) proteins as targets in drug discovery efforts.

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Atypical activation of the G protein Gαq by the oncogenic mutation Q209P

Cited by 33 publications

References 79 publications

Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma

Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma

DAPLE protein inhibits nucleotide exchange on Gαs and Gαq via the same motif that activates Gαi

Heterotrimeric Gq proteins as therapeutic targets?

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