Extended Data Fig. 10: TIE2-PI3K-FOXO1 signaling pathway and its dysregulation in Pik3ca-driven VM.
From: Angiopoietin–TIE2 feedforward circuit promotes PIK3CA-driven venous malformations
PI3K-AKT pathway regulates diverse cellular processes including protein translation (via TSC1/2-mTORC1) and gene transcription through direct (for example, inhibition of FOXO1) or indirect (for example, activation of β-catenin through inhibition of GSK3β) mechanisms. Examples of other AKT targets involved for example, in the regulation of cell survival (BAD) and vascular tone (eNOS) are indicated. FOXO1 inhibition-dependent PI3K signaling contributes to regulation of cellular metabolism, vascular growth and the acquisition of post-capillary venous phenotype. Activation of the PI3K pathway results in “feedforward” signaling to TIE2 by suppressing FOXO1-regulated expression of the autocrine TIE2 antagonist, ANGPT2. The resulting upstream activation of PI3K signaling is reinforced by an increase in coverage by smooth muscle cells (SMCs) that produce the TIE2 agonist, ANGPT1.
