Mutations in the deubiquitinase gene USP8 cause Cushing's disease.
Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein ... binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling.
Mesh Terms:
14-3-3 Proteins, ACTH-Secreting Pituitary Adenoma, Adenoma, Adrenocorticotropic Hormone, Amino Acid Sequence, Animals, COS Cells, Cercopithecus aethiops, Endopeptidases, Endosomal Sorting Complexes Required for Transport, Exome, Gene Expression Regulation, Neoplastic, Humans, Molecular Sequence Data, Mutation, Neoplasm Proteins, Pituitary ACTH Hypersecretion, Pituitary Neoplasms, Pro-Opiomelanocortin, Receptor, Epidermal Growth Factor, Sequence Alignment, Sequence Homology, Amino Acid, Ubiquitin Thiolesterase
14-3-3 Proteins, ACTH-Secreting Pituitary Adenoma, Adenoma, Adrenocorticotropic Hormone, Amino Acid Sequence, Animals, COS Cells, Cercopithecus aethiops, Endopeptidases, Endosomal Sorting Complexes Required for Transport, Exome, Gene Expression Regulation, Neoplastic, Humans, Molecular Sequence Data, Mutation, Neoplasm Proteins, Pituitary ACTH Hypersecretion, Pituitary Neoplasms, Pro-Opiomelanocortin, Receptor, Epidermal Growth Factor, Sequence Alignment, Sequence Homology, Amino Acid, Ubiquitin Thiolesterase
Nat. Genet.
Date: Jan. 01, 2015
PubMed ID: 25485838
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