GPR87 Is an Overexpressed G‐Protein Coupled Receptor in Squamous Cell Carcinoma of the Lung

Gugger, Mathias; White, Richard Allen; Song, Susan; Waser, Bea; Cescato, Renzo; Rivière, Pierre; Reubi, Jean Claude

doi:10.1155/2008/857474

Cited by 60 publications

(51 citation statements)

References 34 publications

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“…For instance, an elevated expression of the orphan G-proteincoupled receptor GPR49 was involved in the formation and proliferation of basal cell carcinoma [176] , while GPR18 was found associated with melanoma metastases [177] . In lung, cervix, skin, urinary bladder, testis, head and neck squamous cell carcinomas were detected high levels of GPR87 [178,179] for which UDP-glucose, cysteinyl-leukotrienes and LPA exhibited binding properties [180] . In breast and colon cancer cells, DNA damage has been recently found to regulate GPR87 expression in a p53-dependent manner [173] .…”

Section: Orphan Gpcrs and Cancermentioning

confidence: 99%

GPCRs and cancer

Lappano

2012

Acta Pharmacol Sin

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G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.

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Section: Orphan Gpcrs and Cancermentioning

confidence: 99%

GPCRs and cancer

Lappano

2012

Acta Pharmacol Sin

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“…LGR4 is up-regulated in the majority of human colon and lung cancers (23)(24)(25). However, the exact roles and mechanisms of RSPO-LGR4 signaling in normal and cancer development remains poorly understood.…”

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confidence: 99%

RSPO–LGR4 functions via IQGAP1 to potentiate Wnt signaling

Carmon

Gong

et al. 2014

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

108

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R-spondins (RSPOs) and their receptor leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4) play pleiotropic roles in normal and cancer development as well as the survival of adult stem cells through potentiation of Wnt signaling. Current evidence indicates that RSPO-LGR4 functions to elevate levels of Wnt receptors through direct inhibition of two membrane-bound E3 ligases (RNF43 and ZNRF3), which otherwise ubiquitinate Wnt receptors for degradation. Whether RSPO-LGR4 is coupled to intracellular signaling proteins to regulate Wnt pathways remains unknown. We identified the intracellular scaffold protein IQ motif containing GTPase-activating protein 1 (IQGAP1) as an LGR4-interacting protein that mediates RSPO-LGR4's interaction with the Wnt signalosome. IQGAP1 binds to and modulates the activities of a plethora of signaling molecules, including MAP kinases, Rho GTPases, and components of the Wnt signaling pathways. Interaction of LGR4 with IQGAP1 brings RSPO-LGR4 to the Wnt signaling complex through enhanced IQGAP1-DVL interaction following RSPO stimulation. In this configuration, RSPO-LGR4-IQGAP1 potentiates β-catenin-dependent signaling by promoting MEK1/2-medidated phosphorylation of LRP5/6 as well as β-catenin-independent signaling through regulation of actin dynamics. Overall, these findings reveal that RSPO-LGR4 not only induces the clearance of RNF43/ZNRF3 to increase Wnt receptor levels but also recruits IQGAP1 into the Wnt signaling complex, leading to potent and robust potentiation of both the canonical and noncanonical pathways of Wnt signaling.cell signaling | receptor activation | adhesion | migration T he four R-spondins (RSPO1-4) and three related leucinerich repeat-containing G-protein coupled receptors, LGR4, LGR5, and LGR6 (LGR4-6), constitute a ligand-receptor system that plays critical roles in development, stem cell survival, and oncogenesis (1-6). Mutations of RSPO1 and RSPO4 affect sex development and nail formation (7-9), respectively, and haplotype insufficiency of LGR4 in humans is associated with several diseases and other traits (10). In the mouse, knockouts of LGR4 or RSPOs are presented with severe developmental abnormalities, including neonatal/embryonic lethality accompanied by hypoplasia and defects in tubule elongation and branching in the kidney, lung, mammary gland, and testis (11-16).LGR5 and LGR6 are markers of adult stem cells in the intestine and other select solid tissues (2).LGR4 is frequently coexpressed with LGR5 or LGR6 and is required for the survival of crypt stem cells in the gut (4, 17). Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of colorectal cancers (18). In mouse mammary tumor virus-induced mouse models of breast and colon cancer, RSPO2 and RSPO3 were identified as two of the most commonly activated alleles (19-21). Ectopic expression of RSPO2/3 in mouse mammary epithelial cells led to an increase in invasiveness in vitro and in tumor formation and metastasis in vivo (20,22). LGR4 is up-reg...

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“…GPR87 is located on human chromosome 3q25 region (Wittenberger et al, 2001) in which the given P2Y receptor genes are clustered. GPR87 are found in neoplastic cells of different location with lung carcinomas (squamous), cervical squamous carcinomas, head and neck squamous cell carcinomas (larynx, pharynx, tonsil and tongue), urinary bladder carcinomas (Glatt et al, 2008;Gugger et al, 2008) and also in the placenta (Wittenberger et al, 2001). Human G-protein coupled receptor 87 (hGPR87) plays a crucial role in intracellular signal transduction (Wittenberger et al, 2001) and normal ovarian development as well as ovarian cancer progression.…”

Section: Introductionmentioning

confidence: 99%

“…Human G-protein coupled receptor 87 (hGPR87) plays a crucial role in intracellular signal transduction (Wittenberger et al, 2001) and normal ovarian development as well as ovarian cancer progression. It was shown to be overexpressed in squamous cell carcinoma (SCCs) or adenocarcinoma in the lung and bladder carcinomas (Gugger et al, 2008). The two most promising reason for targeting this protein are first-GPR87 is the only example of the over expressed GPCRs that can be correlated on a mutation-based level to squamous cell carcinoma of the lung.…”

Section: Introductionmentioning

confidence: 99%

Computational Analysis of the 3-D structure of Human GPR87 Protein: Implications for Structure-Based Drug Design

Rani

Nischal²,

Sahoo³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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The G-protein coupled receptor 87 (GPR87) is a recently discovered orphan GPCR which means that the search of their endogenous ligands has been a novel challenge. GPR87 has been shown to be overexpressed in squamous cell carcinomas (SCCs) or adenocarcinomas in lungs and bladder. The 3D structure of GPR87 was here modeled using two templates (2VT4 and 2ZIY) by a threading method. Functional assignment of GPR87 by SVM revealed that along with transporter activity, various novel functions were predicted. The 3D structure was further validated by comparison with structural features of the templates through Verify-3D, ProSA and ERRAT for determining correct stereochemical parameters. The resulting model was evaluated by Ramachandran plot and good 3D structure compatibility was evidenced by DOPE score. Molecular dynamics simulation and solvation of protein were studied through explicit spherical boundaries with a harmonic restraint membrane water system. A DRY-motif (Asp-Arg-Tyr sequence) was found at the end of transmembrane helix3, where GPCR binds and thus activation of signals is transduced. In a search for better inhibitors of GPR87, in silico modification of some substrate ligands was carried out to form polar interactions with Arg115 and Lys296. Thus, this study provides early insights into the structure of a major drug target for SCCs.

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GPR87 Is an Overexpressed G‐Protein Coupled Receptor in Squamous Cell Carcinoma of the Lung

Cited by 60 publications

References 34 publications

GPCRs and cancer

GPCRs and cancer

RSPO–LGR4 functions via IQGAP1 to potentiate Wnt signaling

Computational Analysis of the 3-D structure of Human GPR87 Protein: Implications for Structure-Based Drug Design

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