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

Apr 7, 2026Cell death and differentiation

Shoc2 controls new lymphatic vessel growth by reducing immune responses linked to mTORC1

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Loss of the protein Shoc2 results in a near-complete loss of lymphatic vasculature.

Shoc2 plays a critical role in the formation of lymphatic vessels.
Depletion of Shoc2 leads to senescence of lymphatic endothelial cells.
Shoc2 is necessary for maintaining a balance in the ERK1/2 signaling pathway.
Increased signaling through mTORC1 occurs when Shoc2 is absent.
Dysregulation of these pathways impairs mitochondrial respiration and activates an immune response, resulting in cellular aging.
A variant of Shoc2 associated with Noonan Syndrome mimics the effects observed with complete Shoc2 loss.

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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.

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

Abstract

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