{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe FEM1A protein, a homolog related to SMIM47 family members, is implicated in skeletal muscle differentiation. Its expression is activated during myocyte differentiation but is notably downregulated in multiple human rhabdomyosarcoma cell lines as well as in several mouse models of this pediatric soft tissue neoplasm, suggesting that FEM1A loss may mark or contribute to a cell fate defect underlying tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSMIM47—also known as EP4 receptor‐associated protein (EPRAP)—functions in peripheral macrophages as a critical anti‐inflammatory mediator. In these cells, activation of the EP4 receptor by prostaglandin E₂ enhances SMIM47/EPRAP activity, which directly interacts with NF‑κB1 p105 to prevent its phosphorylation and degradation. This action stabilizes p105, leading to reduced activation of downstream MAPK and NF‑κB signaling pathways and ultimately suppressing the synthesis of proinflammatory cytokines and chemokines in response to stimuli."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contrast, within the central nervous system, SMIM47/EPRAP appears to have a context‐dependent proinflammatory role. In microglia, this protein facilitates the activation of mitogen‑activated protein kinase (MAPK) signaling cascades—specifically through enhanced MKK4, JNK, and p38 phosphorylation—which in turn promotes the production of proinflammatory cytokines. Notably, deficiency of SMIM47/EPRAP in microglia is associated with diminished cytokine expression and reduced neuronal cell death in response to inflammatory challenges."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, studies in pulmonary inflammation models further underscore the importance of SMIM47/EPRAP in modulating macrophage‐driven inflammation. In bleomycin‑induced lung injury, EPRAP deficiency leads to elevated levels of phosphorylated p105 along with subsequent activation of downstream mediators such as MEK1/2 and ERK1/2, resulting in increased macrophage accumulation and proinflammatory cytokine production; conversely, targeted overexpression of SMIM47/EPRAP in macrophages mitigates these responses. Importantly, posttranslational dephosphorylation by serine phosphatase PP2A appears to be a crucial regulatory step for SMIM47/EPRAP’s anti‐inflammatory function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tereza Ventura-Holman, Heidi Hahn, Jose S Subauste, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Fem1a gene is downregulated in Rhabdomyosarcoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000089261"}], "href": "https://doi.org/10.1159/000089261"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16254458"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16254458"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Manabu Minami, Koichi Shimizu, Yoshihisa Okamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prostaglandin E receptor type 4-associated protein interacts directly with NF-kappaB1 and attenuates macrophage activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M709663200"}], "href": "https://doi.org/10.1074/jbc.M709663200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18270204"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18270204"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajpath.2016.04.002"}], "href": "https://doi.org/10.1016/j.ajpath.2016.04.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27315781"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27315781"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Sei Higuchi, Risako Fujikawa, Taichi Ikedo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EP4 Receptor-Associated Protein in Macrophages Protects against Bleomycin-Induced Pulmonary Inflammation in Mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1502618"}], "href": "https://doi.org/10.4049/jimmunol.1502618"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27799315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27799315"}]}]}]}