Fig. 6: Oncogenic circuit involving FUS-DDIT3, the IGF-IR/PI3K/AKT pathway, and the Hippo/YAP1 axis in MLS.

FUS-DDIT3-dependent induction of IGF2 establishes an autocrine IGF-II/IGF-IR signaling loop, contributing to IGF-IR/PI3K/AKT pathway activation in MLS. IGF-IR and PI3K-transmitted signals interfere with the Hippo kinase LATS1, which is a direct negative regulator of YAP1, thereby promoting nuclear accumulation of transcriptionally active YAP1. In the nucleus, FUS-DDIT3 complexes with YAP1/TEAD. FUS-DDIT3 and YAP1 co-regulate oncogenic gene expression programs affecting proliferation, cell cycle progression, apoptosis, and adipogenesis.