Binding of RAS to PI3Kα regulates developmental and KRASG12D-induced lymphangiogenesis

Area of Science:

• Vascular biology
• Molecular genetics
• Rare diseases

Background:

• Complex lymphatic anomalies (CLAs) are rare developmental disorders of lymphatic vessels.
• Somatic KRAS mutations, particularly KrasG12D, are implicated in CLA pathogenesis by activating MAPK and PI3K signaling pathways.
• The specific role of KRAS-PI3Kα signaling in CLAs is not well understood.

Purpose of the Study:

• To investigate the contribution of RAS-activation of PI3Kα to CLA pathogenesis.
• To elucidate the distinct roles of KRAS/PI3Kα and KRAS/MAPK signaling in lymphatic vascular development and disease.

Main Methods:

• Utilized mouse models with specific mutations in the p110α subunit of PI3Kα to block RAS interaction.
• Analyzed the effects of disrupted RAS-PI3Kα signaling on lymphatic endothelial cells and lymphatic vessel development.
• Examined KrasG12D mutant mice with inhibited or deleted p110α to assess impacts on lymphatic vessel enlargement and valve formation.

Main Results:

• Disrupting RAS-mediated PI3Kα activation in lymphatic endothelial cells impaired lymphatic vessel branching but not valve formation.
• In KrasG12D mutant mice, blocking RAS-PI3Kα signaling reduced pathological lymphatic vessel enlargement.
• However, inhibiting RAS-PI3Kα signaling did not prevent KrasG12D-induced lymphatic valve loss, indicating distinct pathway involvement.

Conclusions:

• KrasG12D signaling diverges into distinct downstream pathways to mediate different CLA phenotypes.
• KRAS/PI3Kα signaling is crucial for pathological lymphatic vessel enlargement in CLAs.
• KRAS/MAPK signaling is primarily responsible for the disruption of lymphatic valve formation in CLAs.