{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DUSP6 (also known as MKP‐3) is a dual‐specificity phosphatase that “turns off” extracellular signal–regulated kinases (ERK1/2) by dephosphorylating critical threonine and tyrosine residues, thereby serving as a key negative feedback regulator of MAPK signaling. This regulation is central to multiple physiological and pathological contexts. For example, in T lymphocytes the age‐dependent increase in DUSP6 expression attenuates T cell receptor–mediated ERK activation, contributing to the decline in T cell responses seen with aging."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the central nervous system, loss of DUSP6 due to upregulation of specific microRNAs (e.g. miR‑125b) has been linked to aberrant ERK activity resulting in tau hyperphosphorylation and features of Alzheimer’s disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cancer, DUSP6 has been shown to act as a tumor suppressor. Reduced or lost expression of DUSP6 in pancreatic tumors is thought to cooperate with activating KRAS mutations to sustain ERK signaling and promote uncontrolled cell growth"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", and similar mechanisms have been observed in non–small‐cell lung cancer, where reduced DUSP6 levels enhance proliferative ERK signals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In ovarian cancer, diminished MKP‐3 (DUSP6) expression is associated with elevated ERK activity, increased cell proliferation, resistance to chemotherapeutic agents, and tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, alterations in DUSP6 (including point mutations) have been implicated as contributory factors in congenital hypogonadotropic hypogonadism, underscoring its role in modulating fibroblast growth factor receptor (FGFR)–dependent signals during development"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", while in squamous cell carcinoma, disruption of DUSP6’s ability to dephosphorylate ERK2—mediated by a long noncoding RNA—results in enhanced MAPK signaling that promotes tumor cell proliferation and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In developmental contexts, extracellular signals such as FGF induce DUSP6 transcription via an ERK‐dependent mechanism that involves binding of Ets family transcription factors to conserved promoter elements; this induction ensures that ERK signaling remains within a physiologically appropriate range to fine‐tune processes such as limb outgrowth and neural patterning."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In addition, studies of the subcellular dynamics of DUSP6 have revealed that its nucleocytoplasmic shuttling—mediated by a specific nuclear export signal independent of its kinase interaction domain—helps dictate the location and duration of ERK dephosphorylation events, thereby impacting the spatiotemporal profile of MAPK signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings emphasize the multifaceted role of DUSP6 in controlling ERK signaling amplitude and duration. Through its action as a negative regulator, DUSP6 influences diverse cellular outcomes including proliferation, apoptosis, differentiation, and tissue homeostasis in both normal physiology and disease.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Guangjin Li, Mingcan Yu, Won-Woo Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.2963"}], "href": "https://doi.org/10.1038/nm.2963"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23023500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23023500"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Julia Banzhaf-Strathmann, Eva Benito, Stephanie May, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.201387576"}], "href": "https://doi.org/10.15252/embj.201387576"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25001178"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25001178"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Toru Furukawa, Makoto Sunamura, Fuyuhiko Motoi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0002-9440(10)64315-5"}], "href": "https://doi.org/10.1016/S0002-9440(10"}, {"type": "t", "text": "64315-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12759238"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12759238"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Zhenfeng Zhang, Susumu Kobayashi, Alain C Borczuk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgq020"}], "href": "https://doi.org/10.1093/carcin/bgq020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20097731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20097731"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "David W Chan, Vincent W S Liu, George S W Tsao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgn167"}], "href": "https://doi.org/10.1093/carcin/bgn167"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18632752"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18632752"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hichem Miraoui, Andrew A Dwyer, Gerasimos P Sykiotis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2013.04.008"}], "href": "https://doi.org/10.1016/j.ajhg.2013.04.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23643382"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23643382"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jian-Jun Xie, Yan-Yi Jiang, Yuan Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Super-Enhancer-Driven Long Non-Coding RNA LINC01503, Regulated by TP63, Is Over-Expressed and Oncogenic in Squamous Cell Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2018.02.018"}], "href": "https://doi.org/10.1053/j.gastro.2018.02.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29454790"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29454790"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Maria Ekerot, Marios P Stavridis, Laurent Delavaine, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20071512"}], "href": "https://doi.org/10.1042/BJ20071512"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18321244"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18321244"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Maria Karlsson, Joanne Mathers, Robin J Dickinson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M406720200"}], "href": "https://doi.org/10.1074/jbc.M406720200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15269220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15269220"}]}]}]}