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Overlap in signaling between constitutively active forms of Smoothened and the α subunit of the heterotrimeric G protein G13

ABSTRACT: RNA sequencing was used to evaluate genes regulated in C3H10T1/2 cells by the Smo agonist purmorphamine

ORGANISM(S): Mus musculus

PROVIDER: GSE111669 | GEO | 2018/05/05

REPOSITORIES: GEO

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Overlap in signaling between Smoothened and the α subunit of the heterotrimeric G protein G13.

Project description: Not available

| S-EPMC5953476 | biostudies-literature

Overlap in signaling between constitutively active forms of Smoothened and the α subunit of the heterotrimeric G protein G13

Project description:Overlap in signaling between constitutively active forms of Smoothened and the α subunit of the heterotrimeric G protein G13

| PRJNA437832 | ENA

Next generation sequencing quantitative analysis of C3H10T1/2 cells treated with purmorphamine, DMSO, purmorphamine and Picoberin or DMSO and Picoberin for 24h, 48h, 96h or 7 days

Project description:Purpose: Analysis of the differential gene expression of C3H10T1/2 cells undergoing Hedgehog (Hh) induced osteoblast differentiation compared to unstimulated (DMSO treated) cells and investigation of the differential gene expression caused by Picoberin, a highly potent inhibitor of Hh induced osteoblast differentiation (Comparison of purmorphamin + Picoberin treated C3H10T1/2 cells with purmorphamin + DMSO treated cells) Methods: 80 % confluent C3H10T1/2 cells were treated either with 1.5 µM purmorphamine + DMSO, only DMSO, 1.5 µM purmorphamine + 1 nM Picoberin, 1.5 µM purmorphamine +100 nM Picoberin or DMSO + 100 nM Picoberin for 24h, 48h, 96h or 7 days. Results: Picoberin inhibits osteoblast differentiation

2022-11-30 | GSE197970 | GEO

Overlap in Signaling through Smoothened and the Heterotrimeric G Protein G13

Project description:RNA sequencing is used to compare genes regulated by a constitutively active form of Smoothened, a protein critical to Hedgehog signaling, and a constitutively active form of the alpha subunit of the heterotrimeric G proteins G13, which shares some of the primary actions of Smoothened.

2018-05-05 | GSE98841 | GEO

Activation of heterotrimeric G proteins by Smoothened.

Project description: Not available

| S-EPMC1567926 | biostudies-literature

Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Subunits

Project description:The Hedgehog (Hh) pathway is essential for tissue homeostasis, and misregulation of this cascade drives several cancers. To control expression of pathway target genes, the G protein-coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase 2 (GRK2)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking vertebrate Hh signal transduction at the membrane to transcription factor activation in the nucleus. In contrast to existing models, our work shows that this aspect of Hh signaling is fundamentally similar between species. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades.

2021-04-25 | PXD019346 | Pride

An essential role for the Gai2 protein in Smoothened-stimulated mammary epithelial cell proliferation

Project description:Hedgehog (Hh) signaling is critical for organogenesis, tissue homeostasis, and stem cell maintenance. Smoothened (SMO), the primary effector of Hh signaling, is expressed ectopically in human breast cancer, as well as in other cancers. Constitutive activation of SMO in mouse mammary glands leads to paracrine stimulation of proliferation, as well as hyperplasia. In canonical signaling, SMO functions via GLI transcription factor activation. However, recent data from Drosophila and mammalian cell lines indicate that SMO can function non-canonically as a G-protein coupled receptor (GPCR) by coupling to heterotrimeric G proteins, particularly those in the pertussis toxin (PTX)-sensitive G-alpha-i (Gai) class. Whether SMO functions as a GPCR in mammalian tissues in vivo is not known. Using genetically modified mouse models, we demonstrate here that SMO-induced stimulation of proliferation is PTX sensitive, and requires Gai2, but not Gai1 or Gai3. Our findings provide evidence for a non-canonical GPCR function of activated SMO in vivo, a finding that may have clinical significance given that most SMO-targeted agents were selected based largely on their ability to block canonical GLI-mediated transcription. Primary mammary epithelial cell RNA was deep-sequenced from mT-mG/SmoM2;MMTV-Cre (EGFP), mT-mG/SmoM2;MMTV-Cre (tdTomato), and mT-mG/SmoM2;+ cells to examine the effects of SmoM2 overexpression in the mammary gland.

2015-09-08 | E-GEOD-70210 | biostudies-arrayexpress

An essential role for the Gai2 protein in Smoothened-stimulated mammary epithelial cell proliferation

2015-09-08 | GSE70210 | GEO

Targeting Hedgehog pathway by Smoothened Antagonist

Project description:Aberrant activation of Hedgehog pathway is responsible for initiation and maintenance of various cancers, including medulloblastoma (MB), basal cell carcinoma (BCC), and other solid and hematological tumors. Therefore, targeting Hh pathway represents promising therapeutic prospects for Hh-driven cancers. In recent years, tremendous efforts have been dedicated to the discovery of Hh pathway inhibitor. While the majority of Hh pathway inhibitors target the upstream membrane protein Smoothened (SMO). Here, we performed Next Generation Sequencing to reveal the target genes of Hh pathway by treating mouse SHH-subtype medulloblastoma cells (SmoWT) with SMO inhibitor (GDC0449) or DMSO.

2021-07-08 | GSE171689 | GEO

Targeting resistance to Smoothened antagonists by inhibiting the PI3K pathway

Project description:Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in sporadic medulloblastoma, the most common brain cancer in children. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for targeted therapy for this tumor. However, acquired resistance has emerged as one of the major challenges of targeted cancer therapy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, after long-term treatment, evidence of acquired resistance was observed. Genome-wide profiling of resistant tumors revealed distinct mechanisms to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, reactivated Hh signaling and restored tumor growth. Analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinosite-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma.

2010-09-29 | GSE19657 | GEO

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