Increased USP8 deubiquitinase activity
trigger
Activating USP8 mutations disrupt normal 14-3-3-dependent control and increase USP8 proteolytic cleavage and catalytic deubiquitinase activity.
Downstream
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Sustained EGFR signaling in corticotrophs
Increased USP8 activity deubiquitinates EGFR, impairing receptor downregulation.
Sustained EGFR signaling in corticotrophs
central effector
Increased USP8-dependent EGFR deubiquitination impairs EGFR downregulation, sustaining EGFR signaling in corticotroph pituitary adenoma cells.
Downstream
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Increased POMC transcriptional activation
Sustained EGFR signaling increases transcriptional activation of POMC.
Increased POMC transcriptional activation
effector
USP8-mutant corticotroph adenoma cells show increased promoter activity of POMC, the precursor gene for ACTH.
Downstream
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Increased corticotropin secretion
Increased POMC transcriptional activation supports excess ACTH production and secretion.
Increased corticotropin secretion
consequence
Corticotroph tumor cells secrete excess ACTH downstream of the USP8-EGFR-POMC axis, producing pituitary ACTH hypersecretion and Cushing disease physiology.