{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAlthough MIR6815 is not directly mentioned in the provided abstracts, integrating the collective findings suggests that MIR6815 may function as a modulator of key receptor‐tyrosine kinase signaling cascades in both neuronal and non‐neuronal contexts. In studies focused on Alzheimer’s disease and Huntington’s disease, adaptor proteins such as those binding the cytoplasmic domain of the beta‐amyloid precursor protein and those mediating BDNF/Trk signaling were shown to promote or attenuate downstream mitogen‐activated protein kinase and cell survival pathways, processes that MIR6815 might influence by modulating the availability or activity of critical docking proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, adaptor proteins such as ShcB, ShcC (also termed N‐Shc or Rai), and other family members are phosphorylated following neurotrophin stimulation through the Trk receptor family. This phosphorylation enables them to engage effectors in the Ras/MAPK and PI3K/AKT pathways, thereby promoting neuronal differentiation, synaptic plasticity, and protecting against excitotoxic or oxidative stress. MIR6815 may function within this network by regulating the expression or stability of these adaptors or their cofactors, thereby indirectly influencing processes such as learning and memory, as well as the modulation of NMDA receptor function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond the central nervous system, several reports indicate that the intricate regulation of cell proliferation, survival, and stress response relies on adaptor proteins and their interacting partners. For example, PHIP1, another molecular interactor, has been implicated in beta‐cell mitogenesis and protection against lipotoxicity, while altered PHIP expression is prognostic in melanomas. In T, B lymphocytes, and astrocytes, the adaptor Rai (ShcC) appears to have a dual role by dampening T cell receptor signals and modulating the inflammatory response in neurodegenerative and autoimmune contexts. Drawing from these diverse studies, MIR6815 is hypothesized to interface with such signaling nodes—potentially by fine‐tuning adaptor protein function and their downstream cascades—to impact cellular metabolism, survival, and immune regulation under stress or disease conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Philip E Tarr, Roberta Roncarati, Giuliana Pelicci, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110286200"}], "href": "https://doi.org/10.1074/jbc.M110286200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11877420"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11877420"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Silvia Ginés, Paola Paoletti, Jordi Alberch "}, {"type": "b", "children": [{"type": "t", "text": "Impaired TrkB-mediated ERK1/2 activation in huntington disease knock-in striatal cells involves reduced p52/p46 Shc expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.084202"}], "href": "https://doi.org/10.1074/jbc.M109.084202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20442398"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20442398"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hui-Yu Liu, Susan O Meakin "}, {"type": "b", "children": [{"type": "t", "text": "ShcB and ShcC activation by the Trk family of receptor tyrosine kinases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111659200"}], "href": "https://doi.org/10.1074/jbc.M111659200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12006576"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12006576"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yoshiaki Miyamoto, Ling Chen, Masahiro Sato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.3030-04.2005"}], "href": "https://doi.org/10.1523/JNEUROSCI.3030-04.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15716419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15716419"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Flavia Troglio, Cinara Echart, Alberto Gobbi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Rai (Shc C) adaptor protein regulates the neuronal stress response and protects against cerebral ischemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0403283101"}], "href": "https://doi.org/10.1073/pnas.0403283101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15494442"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15494442"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Beverly S Colley, Melissa A Cavallin, Kc Biju, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Brain-derived neurotrophic factor modulation of Kv1.3 channel is disregulated by adaptor proteins Grb10 and nShc."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Neurosci (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2202-10-8"}], "href": "https://doi.org/10.1186/1471-2202-10-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19166614"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19166614"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Izumi Miyake, Yuko Hakomori, Yoko Misu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Domain-specific function of ShcC docking protein in neuroblastoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1208523"}], "href": "https://doi.org/10.1038/sj.onc.1208523"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15735675"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15735675"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Alexey Podcheko, Paul Northcott, George Bikopoulos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a WD40 repeat-containing isoform of PHIP as a novel regulator of beta-cell growth and survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.02409-06"}], "href": "https://doi.org/10.1128/MCB.02409-06"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17636024"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17636024"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "David De Semir, Mehdi Nosrati, Vladimir Bezrookove, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1119949109"}], "href": "https://doi.org/10.1073/pnas.1119949109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22511720"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22511720"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Barbara Ortensi, Daniela Osti, Serena Pellegatta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rai is a new regulator of neural progenitor migration and glioblastoma invasion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/stem.1056"}], "href": "https://doi.org/10.1002/stem.1056"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22311806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22311806"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Maria Teresa Savino, Barbara Ortensi, Micol Ferro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rai acts as a negative regulator of autoimmunity by inhibiting antigen receptor signaling and lymphocyte activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.182.1.301"}], "href": "https://doi.org/10.4049/jimmunol.182.1.301"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19109161"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19109161"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Shuai Li, Adam B Francisco, Chunchun Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The full-length isoform of the mouse pleckstrin homology domain-interacting protein (PHIP) is required for postnatal growth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2010.08.042"}], "href": "https://doi.org/10.1016/j.febslet.2010.08.042"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20816727"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20816727"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Micol Ferro, Maria Teresa Savino, Barbara Ortensi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Shc family protein adaptor, Rai, negatively regulates T cell antigen receptor signaling by inhibiting ZAP-70 recruitment and activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0029899"}], "href": "https://doi.org/10.1371/journal.pone.0029899"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22242145"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22242145"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Tommaso Montecchi, Enxhi Shaba, Domiziana De Tommaso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential Proteomic Analysis of Astrocytes and Astrocytes-Derived Extracellular Vesicles from Control and Rai Knockout Mice: Insights into the Mechanisms of Neuroprotection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms22157933"}], "href": "https://doi.org/10.3390/ijms22157933"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34360699"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34360699"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Rungwasee Rattanavich, Andrei Plagov, Dileep Kumar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficit of p66ShcA restores redox-sensitive stress response program in cisplatin-induced acute kidney injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Mol Pathol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexmp.2013.03.001"}], "href": "https://doi.org/10.1016/j.yexmp.2013.03.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23506954"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23506954"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Cristina Ulivieri, Domiziana De Tommaso, Francesca Finetti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A T Cell Suppressive Circuitry Mediated by CD39 and Regulated by ShcC/Rai Is Induced in Astrocytes by Encephalitogenic T Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Immunol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fimmu.2019.01041"}], "href": "https://doi.org/10.3389/fimmu.2019.01041"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31134091"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31134091"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Cristina Ulivieri, Maria Teresa Savino, Ilaria Luccarini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis."}]}, {"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.1502063"}], "href": "https://doi.org/10.4049/jimmunol.1502063"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27288534"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27288534"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Mattia Criscuoli, Cristina Ulivieri, Irene Filippi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Shc protein Rai enhances T-cell survival under hypoxia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.29461"}], "href": "https://doi.org/10.1002/jcp.29461"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31944299"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31944299"}]}]}]}