Identification of FAM3D as a novel endogenous chemotaxis agonist for the FPRs (formyl peptide receptors)

Xiang, Peng; Xu, Enquan; Liang, Weiwei; Pei, Xiaolei; Chen, Dixin; Zheng, Danfeng; Zhang, Yang; Zheng, Chan; Wang, Pingzhang; She, Shaoping; Zhang, Yan; Ma, Jing; Mo, Xiaoning; Zhang, Yingmei; Ma, Dalong

doi:10.1242/jcs.183053

Cited by 38 publications

(37 citation statements)

References 43 publications

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“…FAM3D is part of a family of cytokines containing four genes (FAM3A, FAM3B, FAM3C and FAM3D) that is mainly expressed in highly proliferative tissue such as placenta and the gastrointestinal tract [28]. It has been suggested to play a role in cell proliferation, and functions as an activator of the ERK1/2 and p38MAPK signaling pathways [29]. Finally, the third highly significant CpG (cg03472655) was located in the gene SH2D5 (SH2 Domain Containing 5 protein) which is an adaptor-like protein expressed mainly in the brain [30].…”

Section: Discussionmentioning

confidence: 99%

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Harlid

Kirk

et al. 2019

Epigenetics

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Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10 −7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development.

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Section: Discussionmentioning

confidence: 99%

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Harlid

Kirk

et al. 2019

Epigenetics

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“…Although several previous reports have shown that FAM family members are involved in some biological functions, including the regulation of leukocyte adhesion, migration 3 , 26 , phagocytosis 3 , vascular inflammation 27 , and microglia/macrophage polarization 28 , studies on the functional role of FAM19A5 are limited. In this study, we demonstrated that FAM19A5, an endogenous brain-specific chemokine, strongly inhibited RANKL-induced osteoclast generation, suggesting a novel inhibitory functional role of FAM19A5 in osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

FAM19A5, a brain-specific chemokine, inhibits RANKL-induced osteoclast formation through formyl peptide receptor 2

Park

Kim

Lee

et al. 2017

Sci Rep

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Osteoclasts can be differentiated from bone marrow-derived macrophages (BMDM). They play a key role in bone resorption. Identifying novel molecules that can regulate osteoclastogenesis has been an important issue. In this study, we found that FAM19A5, a neurokine or brain-specific chemokine, strongly stimulated mouse BMDM, resulting in chemotactic migration and inhibition of RANKL-induced osteoclastogenesis. Expression levels of osteoclast-related genes such as RANK, TRAF6, OSCAR, TRAP, Blimp1, c-fos, and NFATc1 were markedly decreased by FAM19A5. However, negative regulators of osteoclastogenesis such as MafB and IRF-8 were upregulated by FAM19A5. FAM19A5 also downregulated expression levels of RANKL-induced fusogenic genes such as OC-STAMP, DC-STAMP, and Atp6v0d2. FAM19A5-induced inhibitory effect on osteoclastogenesis was significantly reversed by a formyl peptide receptor (FPR) 2 antagonist WRW4 or by FPR2-deficiency, suggesting a crucial role of FPR2 in the regulation of osteoclastogenesis. Collectively, our results suggest that FAM19A5 and its target receptor FPR2 can act as novel endogenous ligand/receptor to negatively regulate osteoclastogenesis. They might be regarded as potential targets to control osteoclast formation and bone disorders.

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“…In a more recent study, a new host-derived chemotaxis agonist FAM3D, for the FPR1 and FPR2 was identified [ 135 ]. FAM3D, a cytokine-like protein, is constitutively expressed in the gastrointestinal tract with significant induction in dextran sulfate sodium (DSS)-induced colitis [ 135 ]. FAM3D was found to strongly attract the chemotaxis of human peripheral blood neutrophils and monocytes.…”

Section: Agonists For the Formyl Peptide Receptorsmentioning

confidence: 99%

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

Ye²

2017

Molecules

204

216

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The formyl peptide receptors (FPRs) are G protein-coupled receptors that transduce chemotactic signals in phagocytes and mediate host-defense as well as inflammatory responses including cell adhesion, directed migration, granule release and superoxide production. In recent years, the cellular distribution and biological functions of FPRs have expanded to include additional roles in homeostasis of organ functions and modulation of inflammation. In a prototype, FPRs recognize peptides containing N-formylated methionine such as those produced in bacteria and mitochondria, thereby serving as pattern recognition receptors. The repertoire of FPR ligands, however, has expanded rapidly to include not only N-formyl peptides from microbes but also non-formyl peptides of microbial and host origins, synthetic small molecules and an eicosanoid. How these chemically diverse ligands are recognized by the three human FPRs (FPR1, FPR2 and FPR3) and their murine equivalents is largely unclear. In the absence of crystal structures for the FPRs, site-directed mutagenesis, computer-aided ligand docking and structural simulation have led to the identification of amino acids within FPR1 and FPR2 that interact with several formyl peptides. This review article summarizes the progress made in the understanding of FPR ligand diversity as well as ligand recognition mechanisms used by these receptors.

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Identification of FAM3D as a novel endogenous chemotaxis agonist for the FPRs (formyl peptide receptors)

Cited by 38 publications

References 43 publications

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

FAM19A5, a brain-specific chemokine, inhibits RANKL-induced osteoclast formation through formyl peptide receptor 2

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

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