{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies on immunoglobulin‐like receptors of myeloid cells highlight that members of this receptor family, such as FDF03, contain ITIM motifs that mediate inhibitory signals in innate immunity. For example, FDF03, expressed predominantly by monocytes, macrophages, granulocytes, and dendritic cells, becomes tyrosine phosphorylated upon activation and recruits phosphatases such as SHP-2, leading to dampened calcium mobilization. This paradigm of ITIM-dependent inhibitory signaling serves as an important context for understanding related receptors in the immunoglobulin family."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural investigations of the paired immunoglobulin receptor family have provided key insights into ligand recognition. Crystallographic studies of PILRα and PILRB revealed that, although both adopt a typical siglec fold, subtle differences—most notably the replacement of a tryptophan residue (W108) in PILRα by leucine (L108) in PILRB—result in variant sialic acid (SA) binding avidities. This unique arrangement affects interactions with SA-containing ligands such as HSV-1 glycoprotein B, thereby underscoring the molecular basis for differential ligand recognition within the family."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComplementary research involving related receptors, such as PIRB, shows that ITIM-containing molecules can engage in interactions with intracellular signaling partners, including SH3 domain-containing proteins like HACS1. Although these studies, which mapped binding sites near ITIM motifs and illustrated competitive interactions with SH2 domains, focus on PIRB, they provide a conceptual framework that informs our understanding of how similar ITIM-bearing receptors, including PILRB, might integrate multiple signaling pathways within immune and non-immune cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMore recently, PILRB itself has emerged as an oncogenic player in gastric cancer. In this context, PILRB enhances the PI3K/AKT signaling pathway by directly binding and stabilizing IRS4. It accomplishes this by recruiting the deubiquitinating enzyme OTUB1, which relieves K48-linked ubiquitination of IRS4, thereby protecting IRS4 from proteasomal degradation. This molecular mechanism leads to increased cell proliferation, migration, invasion, and altered cholesterol metabolism, ultimately contributing to tumor growth and resistance to statin treatment. These findings pinpoint PILRB as both a driver of oncogenic signaling and a potential biomarker for therapeutic response in gastric cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "N Fournier, L Chalus, I Durand, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.165.3.1197"}], "href": "https://doi.org/10.4049/jimmunol.165.3.1197"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10903717"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10903717"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Qiong Lu, Guangwen Lu, Jianxun Qi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PILRα and PILRβ have a siglec fold and provide the basis of binding to sialic acid."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1320716111"}], "href": "https://doi.org/10.1073/pnas.1320716111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24843130"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24843130"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jamie J Kwan, Sladjana Slavkovic, Michael Piazza, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HACS1 signaling adaptor protein recognizes a motif in the paired immunoglobulin receptor B cytoplasmic domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Commun Biol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s42003-020-01397-z"}], "href": "https://doi.org/10.1038/s42003-020-01397-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33188360"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33188360"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xing Wang, Yuanyuan Liu, Qiuyan Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PILRB potentiates the PI3K/AKT signaling pathway and reprograms cholesterol metabolism to drive gastric tumorigenesis and metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-024-07026-5"}], "href": "https://doi.org/10.1038/s41419-024-07026-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39227585"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39227585"}]}]}]}