Shoc2 Deficiency Disrupts Lymphangiogenesis through mTOR-Mediated Mitochondrial Dysfunction

Shoc2 is a scaffold protein critical for regulating Raf-1 kinase activation and the amplitude of ERK1/2 signals. Hereditary Shoc2 mutations result in Noonan Syndrome with Loose anagen Hair (NSLH), a debilitating congenital disorder associated with lymphatic abnormalities. We demonstrate that zebrafish Shoc2 null larvae exhibit nearly a complete loss of lymphatic vasculature, suggesting that the Shoc2 gene plays a critical positive role during developmental lymphangiogenesis. The loss of lymphatics caused by Shoc2 deficiency can be rescued by endothelial autonomous expression of Shoc2, confirming its in vivo functional requirement in lymphatic endothelial cells. Shoc2 loss in primary human lymphatic endothelial cells promotes Raptor-mTOR binding and enhances mTORC1 signaling activity. Increased mTORC1 signaling leads to impaired mitochondrial respiration, IRF/IFN-induced signaling, and cell senescence. Notably, expression of the NSLH Shoc2 mutant S2G phenocopies Shoc2 loss, resulting in mTOR activation and increased IFN response. Together, these studies demonstrate the critical role of Shoc2 in lymphangiogenesis and establish a mechanistic link between Shoc2 signaling, mitochondrial function, and lymphangiogenesis, with potential implications for Ras-pathway-related congenital disorders.