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

Area of Science:

• Vascular biology
• Cell signaling
• Molecular genetics

Background:

• Lymphatic vasculature development is essential for fluid homeostasis and immune function.
• Dysregulation of lymphatic development leads to congenital disorders.
• Molecular mechanisms controlling lymphangiogenesis are not fully understood.

Purpose of the Study:

• To investigate the role of the signaling scaffold protein Shoc2 in lymphangiogenesis.
• To elucidate the molecular mechanisms by which Shoc2 regulates lymphatic development.

Main Methods:

• In vivo studies of Shoc2 loss-of-function models.
• In vitro studies using lymphatic endothelial cells.
• Analysis of signaling pathways including ERK1/2 and mTORC1.
• Assessment of mitochondrial function and innate immune responses.

Main Results:

• Loss of Shoc2 resulted in severe defects in lymphatic vasculature formation in vivo.
• Shoc2 deficiency led to senescence of lymphatic endothelial cells in vitro.
• Shoc2 is required for proper ERK1/2 signaling and inhibits mTORC1 signaling.
• Dysregulated signaling impaired mitochondrial respiration and induced an IRF/IFN-II response.
• A Noonan Syndrome variant of Shoc2 mimicked the loss-of-function phenotype.

Conclusions:

• Shoc2 plays a critical, previously unrecognized role in lymphangiogenesis.
• Shoc2 signaling is essential for maintaining lymphatic endothelial cell function and preventing senescence.
• A novel link between Shoc2, mitochondrial respiration, innate immunity, and lymphatic development is established.
• Findings have implications for understanding and treating Ras-pathway-related congenital disorders.