Structural Basis of Latrophilin-FLRT-UNC5 Interaction in Cell Adhesion

Lü, Yue; Nazarko, Olha V.; Sando, Richard; Salzman, Gabriel S.; Li, Nan‐Sheng; Südhof, Thomas C.; Araç, Demet

doi:10.1016/j.str.2015.06.024

Cited by 101 publications

(114 citation statements)

References 40 publications

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“…Understanding of the fundamental architecture of self-cleaved adhesion GPCRs and mechanism of signaling to G proteins has advanced in recent years through solution of aGPCR extracellular region structures and by delineation of the aGPCR tethered-peptideagonist activation mechanism (Arac et al, 2012;Jackson et al, 2015;Liebscher et al, 2014;Lu et al, 2015;Stoveken et al, 2015). Identification and characterization of the diverse protein ligands that bind modules within aGPCR extracellular regions has also contributed to current models that predict physiological aGPCR activation mechanisms (Bolliger et al, 2011;Hamann et al, 1996;Luo et al, 2011;O'Sullivan et al, 2012;Paavola et al, 2014;Petersen et al, 2015;Silva et al, 2011;Stacey et al, 2003;Stephenson et al, 2014;Vallon and Essler, 2006;Xu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Gedunin- and Khivorin-Derivatives Are Small-Molecule Partial Agonists for Adhesion G Protein-Coupled Receptors GPR56/ADGRG1 and GPR114/ADGRG5

et al. 2018

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Adhesion G protein-coupled receptors (aGPCRs) have emerged as potential therapeutic targets in multiple cancers and in neurological diseases. However, there are few modulatory compounds that act on these receptors. The majority of aGPCRs are orphans and a general activation mechanism has only recently been defined: aGPCRs are activated by a tethered agonist. aGPCRs constitutively cleave themselves during biosynthesis to generated two-part receptors comprised of an extracellular domain (ECD) and a 7-transmembrane spanning domain (7TM). ECD dissociation reveals the tethered agonist, initiating G protein signaling. Synthetic peptides that mimic the tethered agonist region can activate aGPCRs. We hypothesized that small molecules could act similarly as peptide agonists. High throughput screening of the 2000 compound Spectrum Collection library using the Serum Response Element luciferase gene reporter assay revealed two related classes of small molecules that could activate the aGPCR GPR56 / ADGRG1. The most potent compound identified was 3-a-acetoxydihydrodeoxygedunin, or 3-a-DOG. 3-a-DOG activated engineered, low-activity GPR56 7TM in independent biochemical and cell-based assays with an EC 50 of ~5 µM. The compound also activated a subset of aGPCRs but not two Class A GPCRs tested. The mode of 3-a-DOG-mediated receptor activation is as a partial agonist. 3-a-DOG activated GPR56 less efficaciously than peptide agonist and could antagonize both the peptide agonist and the endogenous tethered agonist, which are pharmacological hallmarks of partial agonists. Taken together, we have uncovered a novel group of aGPCR partial agonists that will serve as invaluable resources for understanding this unique class receptors.

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Section: Discussionmentioning

confidence: 99%

Gedunin- and Khivorin-Derivatives Are Small-Molecule Partial Agonists for Adhesion G Protein-Coupled Receptors GPR56/ADGRG1 and GPR114/ADGRG5

et al. 2018

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“…Conflicting reports have been published regarding whether or not FLRTs engage in homophilic interactions ( Karaulanov et al, 2006 ; Yamagishi et al, 2011 ; Seiradake et al, 2014 ; Lu et al, 2015 ). Similar to previous experiments that failed to detect binding of soluble FLRT ectodomains to FLRT-expressing cells in culture ( Yamagishi et al, 2011 ) or FLRT-mediated cell aggregation ( Lu et al, 2015 ), we did not observe FLRT homophilic interactions in our biochemical screen or cell aggregation assay. Furthermore, in our stripe assays, FLRT2-expressing SACs and Drd4-GFP ooDSGCs did not respond to FLRT2 stripes.…”

Section: Discussionmentioning

confidence: 99%

An extracellular biochemical screen reveals that FLRTs and Unc5s mediate neuronal subtype recognition in the retina

Visser

Cheng

Perry

et al. 2015

eLife

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In the inner plexiform layer (IPL) of the mouse retina, ~70 neuronal subtypes organize their neurites into an intricate laminar structure that underlies visual processing. To find recognition proteins involved in lamination, we utilized microarray data from 13 subtypes to identify differentially-expressed extracellular proteins and performed a high-throughput biochemical screen. We identified ~50 previously-unknown receptor-ligand pairs, including new interactions among members of the FLRT and Unc5 families. These proteins show laminar-restricted IPL localization and induce attraction and/or repulsion of retinal neurites in culture, placing them in an ideal position to mediate laminar targeting. Consistent with a repulsive role in arbor lamination, we observed complementary expression patterns for one interaction pair, FLRT2-Unc5C, in vivo. Starburst amacrine cells and their synaptic partners, ON-OFF direction-selective ganglion cells, express FLRT2 and are repelled by Unc5C. These data suggest a single molecular mechanism may have been co-opted by synaptic partners to ensure joint laminar restriction.DOI: http://dx.doi.org/10.7554/eLife.08149.001

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“…FLRT proteins are known to interact with several other proteins, such as ROBO1 17 , LPHN3 and UNC5 18, 19 . Through these interactions, FLRTs function as ribonuclease inhibitors 20 , virulence factors 21 , or splicing mediators 22 .…”

Section: Introductionmentioning

confidence: 99%

Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells

Bae

Kim

Lee

et al. 2017

Sci Rep

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To identify dysregulated genes by abnormal methylation and expression in breast cancer, we genome-wide analyzed methylation and expression microarray data from the Gene Expression Omnibus and the Cancer Genome Atlas database. One of the genes screened in silico, FLRT2, showed hypermethylation and downregulation in the cancer dataset and the association was verified both in cultured cell lines and cancer patients’ tissue. To investigate the role of FLRT2 in breast cancer, its expression was knocked down and upregulated in mammary cell lines, and the effect was examined through three levels of approach: pathway analysis; cell activities such as proliferation, colony formation, migration, and adhesion; target gene expression. The top pathway was “Cellular growth and proliferation”, or “Cancer”-related function, with the majority of the genes deregulated in a direction pointing to FLRT2 as a potential tumor suppressor. Concordantly, downregulation of FLRT2 increased cell proliferation and cell migration, while overexpression of FLRT2 had the opposite effect. Notably, cell adhesion was significantly decreased by FLRT2 in the collagen I-coated plate. Taken together, our results provide insights into the role of FLRT2 as a novel tumor suppressor in the breast, which is inactivated by hypermethylation during tumor development.

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Structural Basis of Latrophilin-FLRT-UNC5 Interaction in Cell Adhesion

Cited by 101 publications

References 40 publications

Gedunin- and Khivorin-Derivatives Are Small-Molecule Partial Agonists for Adhesion G Protein-Coupled Receptors GPR56/ADGRG1 and GPR114/ADGRG5

Gedunin- and Khivorin-Derivatives Are Small-Molecule Partial Agonists for Adhesion G Protein-Coupled Receptors GPR56/ADGRG1 and GPR114/ADGRG5

An extracellular biochemical screen reveals that FLRTs and Unc5s mediate neuronal subtype recognition in the retina

Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells

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