A DNA damage and stress inducible G protein-coupled receptor blocks cells in G 2 /M

Self Cite

184

147

G2A is an immunoregulatory G protein-coupled receptor predominantly expressed in lymphocytes and macrophages. Ectopic overexpression studies have implicated G2A as a receptor for the bioactive lysophospholipid, lysophosphatidylcholine (LPC). However, the functional consequences of LPC-G2A interaction at physiological levels of receptor expression, and in a cellular context relevant to its immunological role, remain largely unknown. Here, we show impaired chemotaxis to LPC of a T lymphoid cell line in which G2A expression was chronically down-regulated by RNA interference technology. Rescuing this phenotype by reconstitution of the physiological level of receptor expression further supports a functional connection between LPC-G2A interaction and cellular motility. Overexpression of G2A in the T lymphoid cell line significantly enhanced chemotaxis to LPC. It also modified migration toward the LPC-related molecule, lysophosphatidic acid, indicating the possibility of crosstalk between G2A and endogenous lysophosphatidic acid receptors. The role of G2A in LPCmediated cell migration may be relevant to the autoimmune syndrome associated with genetic inactivation of this G proteincoupled receptor in mice. The experimental system described here can be useful for understanding the structural requirements for LPC recognition by G2A and the signaling pathways regulated by this ligand-receptor pair.

supporting

confidence: 67%

Section: )mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

T cell chemotaxis to lysophosphatidylcholine through the G2A receptor

Radu

Yang

Riedinger

et al. 2003

Self Cite

184

147

“…GPR132/G2A was first described as a transcriptional target of the BCR-ABL tyrosine kinase attenuating B-cell expansion in vitro and arresting cells at G 2 during mitosis (61). Oxidized long-chain fatty acids, lysophosphotidylcholine, 9(S)-HODE and (±)11-HETE have been reported to be potential endogenous ligands of G2A (62,63).…”

Section: Comparative Phylogenetic and Functional Analysis Of Effectormentioning

confidence: 99%

Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist

Cohen

Kang

Chu

et al. 2015

158

151

The trillions of bacteria that make up the human microbiome are believed to encode functions that are important to human health; however, little is known about the specific effectors that commensal bacteria use to interact with the human host. Functional metagenomics provides a systematic means of surveying commensal DNA for genes that encode effector functions. Here, we examine 3,000 Mb of metagenomic DNA cloned from three phenotypically distinct patients for effectors that activate NF-κB, a transcription factor known to play a central role in mediating responses to environmental stimuli. This screen led to the identification of 26 unique commensal bacteria effector genes (Cbegs) that are predicted to encode proteins with diverse catabolic, anabolic, and ligand-binding functions and most frequently interact with either glycans or lipids. Detailed analysis of one effector gene family (Cbeg12) recovered from all three patient libraries found that it encodes for the production of N-acyl-3-hydroxypalmitoyl-glycine (commendamide). This metabolite was also found in culture broth from the commensal bacterium Bacteroides vulgatus, which harbors a gene highly similar to Cbeg12. Commendamide resembles long-chain N-acyl-amides that function as mammalian signaling molecules through activation of G-protein–coupled receptors (GPCRs), which led us to the observation that commendamide activates the GPCR G2A/GPR132. G2A has been implicated in disease models of autoimmunity and atherosclerosis. This study shows the utility of functional metagenomics for identifying potential mechanisms used by commensal bacteria for host interactions and outlines a functional metagenomics-based pipeline for the systematic identification of diverse commensal bacteria effectors that impact host cellular functions.

“…These genes included the primary response gene EBI3, a cytokine homologous to the p40 subunit of IL-12 (31). They also included TDAG8, a putative G protein-coupled receptor in the same family as G2A, a recently cloned receptor with a potential role in cell cycle arrest (32). Also affected were the potential secondary response genes complement receptor 2, STAT-5a, and the mysterious nuclear molecule Jumonji, which plays an important role in development and may be a growth inhibitor (33).…”

Section: Multipathway Dissection Of the Cd40-regulated Expression Resmentioning

confidence: 99%

Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes

Dadgostar

Zarnegar

Hoffmann

et al. 2002

111

CD40͞CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-B pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways. C D40 is a member of the pleiotropic tumor necrosis factor receptor (TNFR) superfamily, which also includes such functionally diverse molecules as CD27, CD30, OX40, RANK, LT-␤R, the p75 low-affinity nerve growth factor receptor, Fas, and members of the death receptor family as well as TNFR1 and TNFR2 (1). CD40 stimulation activates B cells and promotes various aspects of a functional humoral immune response, including enhancement of survival and proliferation (2). Like many TNFR family members, CD40 activates the JNK͞SAPK and NF-B pathways (3, 4). Both of these pathways involve serine͞threonine kinases that regulate gene expression through activation of AP1 and Rel transcription factors, respectively. Another stress-responsive pathway that has also been reported to be activated by CD40 (5) is the p38 kinase pathway, which leads to the phosphorylation and activation of transcription factors such as ATF2 (6). Previous work has also linked CD40 to the activation of the extracellular signal-regulated kinase (ERK)͞mitogen-activated protein kinase (MAPK) pathway (7).In addition to serine͞threonine kinases, a link between CD40 signaling and tyrosine kinase activation has been suggested (8).One pathway shown to be activated by CD40 and to play an important role in CD40 signaling is that initiated by PI-3 kinase (PI-3K) (8-10). PI-3K phosphorylates membrane phospholipids (11), which can recruit and activate pleckstrin homology domaincontaining molecules such as the kinase protein kinase B. This kinase may then regulate the activity of forkhead-related transcription factors (12, 13).In each of the above pathways, one of the major final ...