{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:57:52Z","timestamp":1793041072946,"version":"4.5.0"},"posted":{"date-parts":[[2025,2,1]]},"group-title":"Pathology","reference-count":24,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  SHP2, a protein tyrosine phosphatase (PTP) crucial in Ras-MAPK signaling, is associated with various human congenital diseases and cancers. Here, we show that the catalytically inactive\n                  <jats:italic>\n                    Shp2\n                    <jats:sup>C459S<\/jats:sup>\n                  <\/jats:italic>\n                  mutation results in communicating hydrocephalus, similar to the catalytically activating\n                  <jats:italic>\n                    Shp2\n                    <jats:sup>E76K<\/jats:sup>\n                  <\/jats:italic>\n                  and\n                  <jats:italic>\n                    Mek1\n                    <jats:sup>DD<\/jats:sup>\n                  <\/jats:italic>\n                  mutants. Unlike previous mutants, however,\n                  <jats:italic>\n                    Shp2\n                    <jats:sup>C459S\/+<\/jats:sup>\n                  <\/jats:italic>\n                  mutation uniquely affects ciliary development rather than neurogenesis, leading to reduced cilia density and impaired ciliary motility. Differential scanning fluorimetry revealed that\n                  <jats:italic>\n                    SHP2\n                    <jats:sup>C459S<\/jats:sup>\n                  <\/jats:italic>\n                  , SHP\n                  <jats:italic>\n                    2\n                    <jats:sup>E76K<\/jats:sup>\n                  <\/jats:italic>\n                  and\n                  <jats:italic>\n                    SHP2\n                    <jats:sup>C459S\/E76K<\/jats:sup>\n                  <\/jats:italic>\n                  mutations all induce an open SHP2 conformation, but only\n                  <jats:italic>\n                    SHP2\n                    <jats:sup>C459S<\/jats:sup>\n                  <\/jats:italic>\n                  leads to aberrant GAB1 phosphorylation in cells expressing wild-type SHP2. This distinctive signaling pattern correlates with our observations in brain ventricular tissues of\n                  <jats:italic>\n                    Shp2\n                    <jats:sup>C459S\/+<\/jats:sup>\n                  <\/jats:italic>\n                  mice, where Erk and Stat3 activities remain normal but Gab1 phosphorylation is elevated. Critically, we show that the hydrocephalus phenotype in\n                  <jats:italic>\n                    Shp2\n                    <jats:sup>C459S<\/jats:sup>\n                  <\/jats:italic>\n                  mice can be mitigated by allosteric inhibition of Shp2. These findings suggest that\n                  <jats:italic>Shp2<\/jats:italic>\n                  -associated hydrocephalus is driven by conformational changes rather than altered catalytic activity. Our results underscore the therapeutic potential of conformation-specific allosteric inhibitors in targeting both catalytically active and inactive\n                  <jats:italic>SHP2<\/jats:italic>\n                  mutants.\n                <\/jats:p>","DOI":"10.1101\/2025.01.28.635289","type":"posted-content","created":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T23:20:24Z","timestamp":1738452024000},"source":"Crossref","is-referenced-by-count":3,"title":["Allosteric inhibition rescues hydrocephalus caused by catalytically inactive Shp2"],"prefix":"10.64898","author":[{"given":"Neoklis","family":"Makrides","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilal","family":"Mir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyuan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihua","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Serra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wellington V","family":"Cardoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1186-0626","authenticated-orcid":false,"given":"Neel H.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5555-0825","authenticated-orcid":false,"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025020314150685000_2025.01.28.635289v1.1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.02253-05"},{"key":"2025020314150685000_2025.01.28.635289v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2011.12.038"},{"key":"2025020314150685000_2025.01.28.635289v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr014"},{"key":"2025020314150685000_2025.01.28.635289v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature18621"},{"key":"2025020314150685000_2025.01.28.635289v1.5","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1999.4668"},{"key":"2025020314150685000_2025.01.28.635289v1.6","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl197"},{"key":"2025020314150685000_2025.01.28.635289v1.7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504699200"},{"key":"2025020314150685000_2025.01.28.635289v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06823-9"},{"key":"2025020314150685000_2025.01.28.635289v1.9","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.777926"},{"key":"2025020314150685000_2025.01.28.635289v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2008.07.004"},{"key":"2025020314150685000_2025.01.28.635289v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.01.010"},{"key":"2025020314150685000_2025.01.28.635289v1.12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410012200"},{"key":"2025020314150685000_2025.01.28.635289v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(03)00091-4"},{"key":"2025020314150685000_2025.01.28.635289v1.14","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.1.299-311.2000"},{"key":"2025020314150685000_2025.01.28.635289v1.15","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2017-0436OC"},{"key":"2025020314150685000_2025.01.28.635289v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06814-w"},{"key":"2025020314150685000_2025.01.28.635289v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2023.115300"},{"key":"2025020314150685000_2025.01.28.635289v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2023.168010"},{"key":"2025020314150685000_2025.01.28.635289v1.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2407159121"},{"key":"2025020314150685000_2025.01.28.635289v1.20","doi-asserted-by":"publisher","DOI":"10.1101\/2024.10.20.619055"},{"key":"2025020314150685000_2025.01.28.635289v1.21","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5022"},{"key":"2025020314150685000_2025.01.28.635289v1.22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0405041101"},{"key":"2025020314150685000_2025.01.28.635289v1.23","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aao1591"},{"key":"2025020314150685000_2025.01.28.635289v1.24","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.2c00481"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.01.28.635289","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:57:46Z","timestamp":1768463866000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.01.28.635289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,1]]},"references-count":24,"URL":"https:\/\/doi.org\/10.1101\/2025.01.28.635289","relation":{},"subject":[],"published":{"date-parts":[[2025,2,1]]},"subtype":"preprint"}}