Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses

Authors

• Patricia Wilson, University of KentuckyFollow
• Vishakha Vishwakarma, Eunice Kennedy Shriver National Institute of Child Health and Human Development
• Rebecca Norcross, Clinical Operations R&D group, Zoetis
• Kashmira Khaire, University of California, Los Angeles
• Van N. Pham, Eunice Kennedy Shriver National Institute of Child Health and Human Development
• Brant M. Weinstein, Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentFollow
• Hyun Min Jung, University of Illinois at ChicagoFollow
• Emilia Galperin, University of KentuckyFollow

Abstract

An interplay of growth factors and signaling pathways governs the development and maintenance of lymphatic vasculature, ensuring proper fluid homeostasis and immune function. 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 results in near-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.

Document Type

Article

Publication Date

2026

Notes/Citation Information

© The Author(s) 2026

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41418-026-01730-9

Funding Information

This project was supported by grants from the National Institute of General Medical Sciences (R35GM136295 and 1S10OD025033-01 to EG) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD118715 to EG). BMW was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIA-HD001011 and ZIA-HD008808). This research was supported by the Biostatistics and Bioinformatics and Redox Metabolism Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). Its contents are solely the authors’ responsibility and do not necessarily represent the official views of the National Institute of Health. HMJ was supported by the UIC College of Medicine start-up fund.

Repository Citation

Wilson, Patricia; Vishwakarma, Vishakha; Norcross, Rebecca; Khaire, Kashmira; Pham, Van N.; Weinstein, Brant M.; Jung, Hyun Min; and Galperin, Emilia, "Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses" (2026). Molecular and Cellular Biochemistry Faculty Publications. 211.
https://uknowledge.uky.edu/biochem_facpub/211