Dataset Information

The Adhesion G-Protein-Coupled Receptor, GPR56/ADGRG1, Inhibits Cell-Extracellular Matrix Signaling to Prevent Metastatic Melanoma Growth.

ABSTRACT: Metastatic growth is considered a rate-limiting step in cancer progression, and upregulation of extracellular matrix (ECM) deposition and cell-ECM signaling are major drivers of this process. Mechanisms to reverse ECM upregulation in cancer could potentially facilitate its prevention and treatment but they are poorly understood. We previously reported that the adhesion G-protein-coupled receptor GPR56/ADGRG1 is downregulated in melanoma metastases. Its re-expression inhibited melanoma growth and metastasis and reduced the deposition of fibronectin, a major ECM component. We hypothesize that its effect on fibronectin deposition contributes to its inhibitory role on metastatic growth. To test this, we investigated the function of GPR56 on cell-fibronectin adhesion and its relationship with metastatic growth in melanoma. Our results reveal that GPR56 inhibits melanoma metastatic growth by impeding the expansion of micrometastases to macrometastases. Meanwhile, we present evidence that GPR56 inhibits fibronectin deposition and its downstream signaling, such as phosphorylation of focal adhesion kinase (FAK), during this process. Administration of the FAK inhibitor Y15 perturbed the proliferation of melanoma metastases, supporting a causative link between the cell adhesion defect induced by GPR56 and its inhibition of metastatic growth. Taken together, our results suggest that GPR56 in melanoma metastases inhibits ECM accumulation and adhesion, which contributes to its negative effects on metastatic growth.

SUBMITTER: Millar MW

PROVIDER: S-EPMC5799216 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

The Adhesion G-Protein-Coupled Receptor, GPR56/ADGRG1, Inhibits Cell-Extracellular Matrix Signaling to Prevent Metastatic Melanoma Growth.

Millar Michelle W MW Corson Nancy N Xu Lei L

Frontiers in oncology 20180201

Metastatic growth is considered a rate-limiting step in cancer progression, and upregulation of extracellular matrix (ECM) deposition and cell-ECM signaling are major drivers of this process. Mechanisms to reverse ECM upregulation in cancer could potentially facilitate its prevention and treatment but they are poorly understood. We previously reported that the adhesion G-protein-coupled receptor GPR56/ADGRG1 is downregulated in melanoma metastases. Its re-expression inhibited melanoma growth and ...[more]

PMID: 29450192

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Project description:GPR56 is a widely expressed adhesion GPCR (AGPCR) that has pleotropic roles in brain development, platelet function, cancer, and more. Nearly all AGPCRs possess extracellular regions that bind protein ligands and conceal a cryptic tethered peptide agonist. AGPCR reception of mechanical or shear force is thought to release the tethered agonist permitting its binding to the AGPCR orthosteric site for consequent activation of G protein signaling. This multistep mechanism of AGPCR activation is difficult to target, emphasizing the need for tool compounds and potential therapeutics that modulate AGPCRs directly. We expanded our cell-based pilot screen for GPR56 small molecule activators to screen >200,000 compounds and identified two promising agonists: 2-(furan-2-yl)-1-[(4-phenylphenyl)carbonyl]pyrrolidine, or compound 4, and propan-2-yl-4-(2-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, or compound 36. Both compounds activated GPR56 receptors enginered to have impaired tethered agonists and/or be cleavage deficient. Compound 4 activated a subset of group VIII AGPCRs while compound 36 had exclusive specificity for GPR56 among the GPCRs tested. Compound 36 SAR analysis identified an analog with the isopropyl R group replaced with a cyclopentyl ring and the electrophilic bromine replaced with a CF3 group. Analog 36.40 had 40% increased potency over compound 36 and was 20-fold more potent than synthetic peptidomimetics designed from the GPR56 tethered agonist. The new GPCR56 tool compounds discovered in this screen may be used to further advance understanding of GPR56 function and aid development of AGPCR-targeted therapeutics. SIGNIFICANCE STATEMENT: Adhesion G protein coupled receptors (AGPCRs) are a large, clinically relevant class of GPCRs with no available therapeutics, in part due to their unique mechanism of activation. GPR56 is a widely expressed model AGPCR involved in cancer metastasis, hemostasis, and neuron myelination. In the present study, we identified novel small molecule agonists for GPR56. These molecules are among the most potent identified thus far and may become useful leads in the development of a GPR56-targeted therapeutic.

Dataset Information

The Adhesion G-Protein-Coupled Receptor, GPR56/ADGRG1, Inhibits Cell-Extracellular Matrix Signaling to Prevent Metastatic Melanoma Growth.

Publications

The Adhesion G-Protein-Coupled Receptor, GPR56/ADGRG1, Inhibits Cell-Extracellular Matrix Signaling to Prevent Metastatic Melanoma Growth.

Similar Datasets

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