{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FRS3—also known as FRS2β or SNT‐2—functions as an intracellular adaptor that modulates multiple receptor tyrosine kinase signals, most notably those initiated by fibroblast growth factor receptors, neurotrophin receptors, and related oncogenic kinases. In thyroid cancer models, FRS3 is recruited by TRK oncoproteins through the same phosphotyrosine motif that engages Shc and FRS2, suggesting that its participation in signal transmission may contribute to thyroid carcinogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, studies in breast cancer have identified a chromosomal region containing FRS3 where genetic variation associates with patient survival, thereby implicating FRS3 in the modulation of tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of growth factor signaling, FRS3 appears to exert a negative regulatory influence on epidermal growth factor receptor (EGFR) family responses. Its capacity to bind ERK2 and to anchor activated ERK at the plasma membrane underlies inhibitory effects on EGFR‐induced cell transformation and proliferation; moreover, reduced FRS3 expression correlates with poorer prognosis in non–small cell lung cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, by modulating the interplay between Rnd1 and RhoA upon FGF receptor activation, FRS3 participates in the regulation of cytoskeletal dynamics that affect neurite outgrowth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Developmental studies extend these functions. In Xenopus, knockdown of the Frs3 homolog disrupts FGF/IGF‐induced extracellular signal–regulated kinase (ERK) activation and impairs eye development, with the critical role mapped to its Shp2‐binding sites."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In primary cortical neurons, however, overexpression of FRS3 does not promote neurite extension in contrast to its paralog FRS2, indicating that FRS3 may serve distinct, possibly inhibitory, roles in neuronal differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Expression analyses during embryogenesis further reveal that FRS3 is more spatially restricted than FRS2—being prominently detected in the developing neural tube, heart, stomach, and liver—implying specialized functions in organogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, in a study of renal cell carcinoma, FRS3 emerged among a set of insulin receptor–associated genes whose expression is downregulated upon insulin and IGF stimulation, suggesting a potential role for FRS3 in the crosstalk between metabolic signaling and tumorigenesis in renal tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Valeria Ranzi, Susan O Meakin, Claudia Miranda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The signaling adapters fibroblast growth factor receptor substrate 2 and 3 are activated by the thyroid TRK oncoproteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2002-221002"}], "href": "https://doi.org/10.1210/en.2002-221002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12586769"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12586769"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Elizabeth M Azzato, Kristy E Driver, Fabienne Lesueur, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/bcr2100"}], "href": "https://doi.org/10.1186/bcr2100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18507837"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18507837"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "L Huang, M Watanabe, M Chikamori, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Unique role of SNT-2/FRS2beta/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1209656"}], "href": "https://doi.org/10.1038/sj.onc.1209656"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16702953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16702953"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "D Iejima, Y Minegishi, K Takenaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FRS2beta, a potential prognostic gene for non-small cell lung cancer, encodes a feedback inhibitor of EGF receptor family members by ERK binding."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2010.69"}], "href": "https://doi.org/10.1038/onc.2010.69"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20228838"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20228838"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Amane Harada, Hironori Katoh, Manabu Negishi "}, {"type": "b", "children": [{"type": "t", "text": "Direct interaction of Rnd1 with FRS2 beta regulates Rnd1-induced down-regulation of RhoA activity and is involved in fibroblast growth factor-induced neurite outgrowth in PC12 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M411356200"}], "href": "https://doi.org/10.1074/jbc.M411356200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15738000"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15738000"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yeon-Jin Kim, Minjin Bahn, Yong Hwan Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Xenopus laevis FGF receptor substrate 3 (XFrs3) is important for eye development and mediates Pax6 expression in lens placode through its Shp2-binding sites."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2014.10.019"}], "href": "https://doi.org/10.1016/j.ydbio.2014.10.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25446028"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25446028"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Li Zhou, Asghar Talebian, Susan O Meakin "}, {"type": "b", "children": [{"type": "t", "text": "The signaling adapter, FRS2, facilitates neuronal branching in primary cortical neurons via both Grb2- and Shp2-dependent mechanisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Neurosci (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12031-014-0406-4"}], "href": "https://doi.org/10.1007/s12031-014-0406-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25159185"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25159185"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "K McDougall, C Kubu, J M Verdi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Developmental expression patterns of the signaling adapters FRS-2 and FRS-3 during early embryogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mech Dev (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0925-4773(01)00337-9"}], "href": "https://doi.org/10.1016/s0925-4773(01"}, {"type": "t", "text": "00337-9) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11335123"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11335123"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Wojciech Solarek, Michal Koper, Slawomir Lewicki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Insulin and insulin-like growth factors act as renal cell cancer intratumoral regulators."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Commun Signal (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12079-019-00512-y"}], "href": "https://doi.org/10.1007/s12079-019-00512-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30929166"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30929166"}]}]}]}