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Disruption of these regulatory mechanisms can lead to congenital lymphatic disorders and contribute to various pathological conditions. However, the mechanisms underlying the molecular regulation of these processes remain elusive. Here we reveal a critical and previously unappreciated role for the signaling scaffold protein Shoc2 in lymphangiogenesis. We demonstrate that loss of Shoc2 leads to nearly a complete loss of lymphatic vasculature in vivo and senescence of lymphatic endothelial cells in vitro. Mechanistically, Shoc2 is required for balancing signaling through the ERK1\/2 pathway, and its loss results in increased mTORC1 signaling. This dysregulation impairs mitochondrial respiration and triggers an IRF\/IFN-II response, ultimately leading to cellular senescence. Strikingly, expression of the Noonan Syndrome with Loose anagen Hair (NSLH)-causing Shoc2 variant S2G phenocopies the effects of Shoc2 loss. Together, these studies establish the critical role of Shoc2 in lymphangiogenesis and uncover a novel mechanistic link between Shoc2 signaling, mitochondrial function, innate immune response, and lymphatic development, with significant implications for Ras-pathway-related congenital disorders.<\/jats:p>","DOI":"10.1101\/2025.03.26.645567","type":"posted-content","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T02:11:09Z","timestamp":1743300669000},"source":"Crossref","is-referenced-by-count":2,"title":["Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses"],"prefix":"10.64898","author":[{"given":"Patricia","family":"Wilson","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishakha","family":"Vishwakarma","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Norcross","sequence":"additional","affiliation":[{"name":"Clinical Operations R&D group, Zoetis, Kalamazoo, MI, 49001"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kashmira","family":"Khaire","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Developmental Biology, University of California, Los Angeles, CA, 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Van N.","family":"Pham","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brant M.","family":"Weinstein","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Min","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8743-026X","authenticated-orcid":false,"given":"Emilia","family":"Galperin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041205554835000_2025.03.26.645567v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01723-x"},{"key":"2026041205554835000_2025.03.26.645567v2.2","doi-asserted-by":"crossref","unstructured":"Petrova TV , Koh GY . 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