GPCR Somatostatin Receptor Extracellular Loop 2 Is a Key Ectodomain for Making Subtype-Selective Antibodies With Agonist-Like Activities in the Pancreatic Neuroendocrine Tumor BON Cell Line

Leu, Frank; Nandi, Minesh

doi:10.1097/mpa.0b013e3181de8c05

Cited by 9 publications

(7 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We paid major attention to the G-protein-coupled receptors (GPCRs) signaling transducer, underlining the importance of these receptors in endocrine and neuroendocrine cells 30, 31, 32, 33 in terms of signal-transduction mechanisms. We have previously investigated GPCRs, such as the olfactory receptor 51 E1 (OR51E1), which has been reported as a potential novel carcinoma marker of small intestinal neuroendocrine tumors, as its restriction in terms of mRNA expression in normal enterochromaffin cell and tumor cells compared with a variety of different normal tissues.…”

Section: Discussionmentioning

confidence: 99%

Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors

et al. 2013

View full text Add to dashboard Cite

Well-differentiated small intestinal neuroendocrine tumors are rare malignancies. They arise from enterochromaffin cells and very little is known about differential microRNA (miRNA) expression. The aim of this study was to identify the miRNA profile of well-differentiated small intestinal neuroendocrine tumors, which may have a critical role in tumor development, progression and potentially develop miRNAs as novel clinical biomarkers. Specimens from two test groups, 24 small intestinal neuroendocrine tumor specimens at different stages of malignancy, are included in this study. Total RNA from the first test group, five primary tumors, five mesentery metastases and five liver metastases was hybridized onto the Affymetrix Genechip miRNA arrays to perform a genome-wide profile. The results were validated by using quantitative real-time PCR (QRT-PCR) and northern blot analyses. We then expanded the investigation to laser capture microdissected small intestinal neuroendocrine tumor cells and immuno-laser capture microdissected normal enterochromaffin cells of the first test group. Furthermore, a second test group, three primary tumors, three mesentery metastases and three liver metastases, was included in the study. Thus, two independent test groups validated the data by QRT-PCR. Moreover, we characterized nine miRNAs, five (miR-96, -182, -183, -196a and -200a), which are upregulated during tumor progression, whereas four (miR-31, -129-5p, -133a and -215) are downregulated. Several online software programs were used to predict potential miRNA target genes to map a number of putative target genes for the aberrantly regulated miRNAs, through an advanced and novel bioinformatics analysis. Our findings provide information about pivotal miRNAs, which may lead to further insights into tumorigenesis, progression mechanisms and novel therapeutic targets recognition.

show abstract

Section: Discussionmentioning

confidence: 99%

Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Allosteric modulation involving ECL2 has been shown for the M1R through interactions with another tyrosine residue (Y179) and a phenylalanine residue (F182) (Abdul-Ridha et al, 2014). ECL2 in the somatostatin receptors has been used as a successful antibody target to induce an agonist-like response (Leu and Nandi, 2010).…”

Section: Ecl2 Is a Proposed Site Of Allosteric Modulationmentioning

confidence: 99%

Understanding the common themes and diverse roles of the second extracellular loop (ECL2) of the GPCR super-family

Woolley

Conner

2017

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

The extracellular loops (ECLs) of G protein-coupled receptors (GPCRs) can bind directly to docked orthosteric or allosteric ligands, they can contain transient contact points for ligand entry into the transmembrane (TM) bundle and they can regulate the activation of the receptor signalling pathways. Of the three ECLs, ECL2 is the largest and most structurally diverse reflecting its functional importance. This has been shown through biochemical techniques and has been supported by the many subsequent crystal structures of GPCRs bound to both agonists and antagonists. ECL2 shares common structural features between (and sometimes across) receptor sub-families and can facilitate ligand entry to the TM core or act directly as a surface of the ligand-binding pocket. Structural similarities seem to underpin common binding mechanisms; however, where these exist, variations in primary sequence ensure ligand-binding specificity. This review will compare current understanding of the structural themes and main functional roles of ECL2 in ligand binding, activation and regulation of the major families of GPCRs.

show abstract

“…In the case of the somatostatin receptors (SSTR), antibodies directed against their ECL2 have agonistic-like properties, while having no effect on agonist binding to receptors. SSTR2, SSTR3, and SSTR5 selective antibodies were also shown to diminish cAMP production and decrease serotonin secretion leading to a suppressed proliferation of neuroendocrine tumor cells (36). Moreover, specific antibodies against the ECL2 of the CCR5 were shown to block HIV entry in cells (38).…”

Section: Targeting Gpcr Domains For Allosterically Biasing Receptor Smentioning

confidence: 99%

Allosteric and Biased G Protein-Coupled Receptor Signaling Regulation: Potentials for New Therapeutics

Khoury

Clement²,

Laporte

2014

Front. Endocrinol.

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that participate in many aspects of the endocrine function and are important targets for drug development. They transduce signals mainly, but not exclusively, via hetero-trimeric G proteins, leading to a diversity of intracellular signaling cascades. Ligands binding at the hormone orthosteric sites of receptors have been classified as agonists, antagonists, and/or inverse agonists based on their ability to mainly modulate G protein signaling. Accumulating evidence also indicates that such ligands, alone or in combination with other ones such as those acting outside the orthosteric hormone binding sites (e.g., allosteric modulators), have the ability to selectively engage subsets of signaling responses as compared to the natural endogenous ligands. Such modes of functioning have been variously referred to as “functional selectivity” or “ligand-biased signaling.” In this review, we provide an overview of the current knowledge regarding GPCR-biased signaling and their functional regulation with a focus on the evolving concept that receptor domains can also be targeted to allosterically bias signaling, and discuss the usefulness of such modes of regulation for the design of more efficient therapeutics.

show abstract

GPCR Somatostatin Receptor Extracellular Loop 2 Is a Key Ectodomain for Making Subtype-Selective Antibodies With Agonist-Like Activities in the Pancreatic Neuroendocrine Tumor BON Cell Line

Cited by 9 publications

References 46 publications

Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors

Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors

Understanding the common themes and diverse roles of the second extracellular loop (ECL2) of the GPCR super-family

Allosteric and Biased G Protein-Coupled Receptor Signaling Regulation: Potentials for New Therapeutics

Contact Info

Product

Resources

About