Figure 5
From: Recurrent gain-of-function USP8 mutations in Cushing's disease
Mechanisms of USP8 mutation-mediated ACTH hyperproduction. The deubiquitinating enzyme USP8 can be phosphorylated allowing for association with 14-3-3 protein, which subsequently inhibits its activity. USP8 mutant fails to bind 14-3-3 protein, leading to an elevated USP8 activity. USP8 deubiquitinates numerous targets and protect them from degradation. EGFR is an crucial USP8 target, and deregulation of EGFR leads to increased MAPK signaling and subsequently promotes POMC transcription partially through inducing the degradation of p27(Kip1), perhaps other regulators such as Brg1 and HDAC2. USP8 also regulates other RTKs such as c-MET and ErbB3, both of which potentially play a role in ACTH production. Finally, through regulating Smoothened expression and cellular location, USP8 mutation activates Hedgehog signaling, resulting in ACTH secretion. Therefore, inhibiting USP8 and/or EGFR activity represents a potential therapeutic approach for Cushing's disease.
