The GPS Motif Is a Molecular Switch for Bimodal Activities of Adhesion Class G Protein-Coupled Receptors

Prömel, Simone; Frickenhaus, Marie; Hughes, Samantha Jane; Mestek, Lamia; Staunton, David; Woollard, Alison; Vakonakis, Ioannis; Schöneberg, Torsten; Schnabel, Ralf; Russ, Andreas; Langenhan, Tobias

doi:10.1016/j.celrep.2012.09.012

Cited by 23 publications

(64 citation statements)

References 28 publications

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“…It is required for cleavage of aGPCR pro-receptor molecules and mediates noncovalent reassociation of the cleaved fragments (Arac et al, 2012). However, GPS cleavage is dispensable for aGPCR function and the consensus GPS sequence is frequently lost in individual aGPCR homologs (Pr€ omel et al, 2012). Thus, the physiological relevance of GPS cleavage and the functional difference between cleavable versus noncleavable aGPCR have remained controversial to date.…”

Section: Gpr111 and Gpr115 Are Not Autoproteolyzed At The Gps Motifmentioning

confidence: 99%

“…We have used this strategy to systematically uncover the requirement of conserved protein domains in the N terminus of the latrophilin-type aGPCR LAT-1 (Vakonakis et al, 2008;Langenhan et al, 2009). Using this approach, we have recently shown that cleavage at the GPS motif is not necessary for activity of LAT-1 in development and fertility, that the ''splitpersonality'' hypothesis, the ambiguous pairing of cleaved N-and C-terminal subunits of different aGPCR (Silva et al, 2009), is not required for LAT-1 function in the worm, and that two different signal activities are relayed through the LAT-1 receptor (Pr€ omel et al, 2012). In addition to dissecting molecular dependencies of aGPCR signals, the worm also permits analysis of genetic interactions for the two invertebrate aGPCR groups, latrophilins and Flamingo/CELSR, under physiological conditions.…”

Section: Introductionmentioning

confidence: 99%

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Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

Prömel

Waller-Evans

Dixon

et al. 2012

Developmental Dynamics

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Background: Adhesion G protein-coupled receptors (aGPCR) constitute a structurally and functionally diverse class of seven-transmembrane receptor proteins. Although for some of the members important roles in immunology, neurology, as well as developmental biology have been suggested, most receptors have been poorly characterized. Results: We have studied evolution, expression, and function of an entire receptor group containing four uncharacterized aGPCR: Gpr110, Gpr111, Gpr115, and Gpr116. We show that the genomic loci of these four receptors are clustered tightly together in mouse and human genomes and that this cluster likely derives from a single common ancestor gene. Using transcriptional profiling on wild-type and knockout/LacZ reporter knockin mice strains, we have obtained detailed expression maps that show ubiquitous expression of Gpr116, co-expression of Gpr111 and Gpr115 in developing skin, and expression of Gpr110 in adult kidney. Loss of Gpr110, Gpr111, or Gpr115 function did not result in detectable defects, indicating that genes of this aGPCR group might function redundantly. Conclusions: The aGPCR cluster Gpr110, Gpr111, Gpr115, and Gpr116 developed from one common ancestor in vertebrates. Expression suggests a role in epithelia, and one can speculate about a possible redundant function of GPR111 and GPR115. Developmental Dynamics 241:1591-1602, 2012.V C 2012 Wiley Periodicals, Inc.

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Section: Gpr111 and Gpr115 Are Not Autoproteolyzed At The Gps Motifmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

Prömel

Waller-Evans

Dixon

et al. 2012

Developmental Dynamics

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“…We demonstrated that the receptor is activated by a 13 amino acid short intrinsic sequence located in the extracellular N terminus. Based on several lines of experimental evidence 14 we speculate that this intrinsic activation occurs by structural changes within the receptor upon binding to a yet unknown extracellular agonist and interaction of this sequence with the 7 transmembrane region (Fig. 2).…”

Section: Lat-1 Mediates a G S Protein/adenylyl Cyclase/ Camp Signal Umentioning

confidence: 99%

“…18 Our previous analyses revealed that the receptor mediates its function in spindle orientation via a signaling mode depending on its 7 transmembrane domain suggesting a classical GPCR signal involving heterotrimeric G proteins. 6,14 To address this question we employed an in vitro assay system based on heterologous expression of lat-1 and observed functional G-protein coupling of the receptor to the 3 major G proteins G s , G q and G i by measuring second messengers. Due to the high conservation of these G proteins among metazoan species 19 heterologous coupling of these to the nematode receptor is possible.…”

Section: Lat-1 Mediates a G S Protein/adenylyl Cyclase/ Camp Signal Umentioning

confidence: 99%

“…6,14 However, its role in oriented cell division and anterior-posterior polarity is the most thoroughly studied one. Nematodes homozygous for the null mutant allele lat-1(ok1465) (referred to lat-1 hereafter) show severe defects in embryonic and larval development leading to only a small number of individuals passing developmental stages and reaching adulthood.…”

Section: Introductionmentioning

confidence: 99%

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The adhesion GPCR latrophilin – a novel signaling cascade in oriented cell division and anterior-posterior polarity

Winkler

Prömel

2016

Worm

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Although several signaling pathways in oriented cell division have been well characterized such as delta/notch inductions or wnt/frizzled-based anterior-posterior polarity, there is strong evidence for additional signal pathways controlling early anterior-posterior polarity decisions. The homolog of the adhesion G protein-coupled receptor latrophilin, LAT-1 has been identified as a receptor essential for oriented cell division in an anterior-posterior direction of specific blastomeres in the early C. elegans embryo. We recently conducted a study aiming at clarifying the signals involved in LAT-1 function. We identified a G s protein/adenylyl cyclase/cAMP pathway in vitro and demonstrated its physiological relevance in oriented cell division. By interaction with a G s protein LAT-1 elevates cAMP levels. These data indicate that G-protein signaling in oriented cell division is not solely GPCR-independent. This commentary will discuss our findings in the context of the current knowledge of mechanisms controlling oriented cell division and anterior-posterior polarity. Further, we identify open questions which need to be addressed in the future.

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Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans

Vetrini

D’Alessandro

Akdemir

et al. 2016

The American Journal of Human Genetics

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Disruption of the establishment of left-right (L-R) asymmetry leads to situs anomalies ranging from situs inversus totalis (SIT) to situs ambiguus (heterotaxy). The genetic causes of laterality defects in humans are highly heterogeneous. Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families. PKD1L1 encodes a polycystin-1-like protein and its loss of function is known to cause laterality defects in mouse and medaka fish models. Family 1 had one fetus and one deceased child with heterotaxy and complex congenital heart malformations. WES identified a homozygous splicing mutation, c.6473+2_6473+3delTG, which disrupts the invariant splice donor site in intron 42, in both affected individuals. In the second family, a homozygous c.5072G>C (p.Cys1691Ser) missense mutation was detected in an individual with SIT and congenital heart disease. The p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the G protein-coupled receptor proteolytic site (GPS) motif. Damaging effects associated with substitutions of this conserved cysteine residue in the GPS motif have also been reported in other genes, namely GPR56, BAI3, and PKD1 in human and lat-1 in C. elegans, further supporting the likely pathogenicity of p.Cys1691Ser in PKD1L1. The identification of bi-allelic PKD1L1 mutations recapitulates previous findings regarding phenotypic consequences of loss of function of the orthologous genes in mice and medaka fish and further expands our understanding of genetic contributions to laterality defects in humans.

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The GPS Motif Is a Molecular Switch for Bimodal Activities of Adhesion Class G Protein-Coupled Receptors

Cited by 23 publications

References 28 publications

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

The adhesion GPCR latrophilin – a novel signaling cascade in oriented cell division and anterior-posterior polarity

Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans

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