The molecular basis of ubiquitin-specific protease 8 autoinhibition by the WW-like domain

Kakihara, Keijun; Asamizu, Kengo; Moritsugu, Kei; Kubo, Masahide; Kitaguchi, Tetsuya; Endo, Akinori; Kidera, Akinori; Ikeguchi, Mitsunori; Kato, Akira; Komada, Masayuki; Fukushima, Toshiaki

doi:10.1101/2021.05.31.446389

Cited by 2 publications

(2 citation statements)

References 61 publications

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“…One recently found mutation is also located in exon 14 upstream to the 14‐3‐3 binding motif 85 . In the wild‐type protein, 14‐3‐3 binding causes conformational changes that enable USP8 to block its own catalytic activity 86 . Loss in the 14‐3‐3 binding motif in the USP8 mutants enhances their deubiquitinase activity and enables access to proteases that cleave it to a C‐terminal 40‐KD fragment with high catalytic capacity 65,87 .…”

Section: Sporadicmentioning

confidence: 99%

“…85 In the wild-type protein, 14-3-3 binding causes conformational changes that enable USP8 to block its own catalytic activity. 86 Loss in the 14-3-3 binding motif in the USP8 mutants enhances their deubiquitinase activity and enables access to proteases that cleave it to a C-terminal 40-KD fragment with high catalytic capacity. 65,87 Indeed, USP8 mutants show loss of 14-3-3 binding and higher deubiquitinase activity in vitro compared to wild-type protein.…”

Section: Ubiquitin Specific Protease 8 (Usp8)mentioning

confidence: 99%

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Genetics of Cushing's disease

Simon

Theodoropoulou

2022

J Neuroendocrinology

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Corticotroph tumours are primarily sporadic monoclonal neoplasms and only rarely found in genetic syndromes. Recurrent mutations in the ubiquitin specific protease 8 (USP8) gene are found in around half of cases. Mutations in other genes such as USP48 and NR3C1 are less frequent, found in less than ~20% of cases. TP53 and ATXR mutations are reported in up to one out of four cases, when focusing in USP8 wild type or aggressive corticotroph tumours and carcinomas. At present, USP8 mutations are the primary driver alterations in sporadic corticotroph tumours, TP53 and ATXR mutations may indicate transition to more aggressive tumour phenotype. Next generation sequencing efforts have identified additional genomic alterations, whose role and importance in corticotroph tumorigenesis remains to be elucidated.

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Section: Sporadicmentioning

confidence: 99%

Section: Ubiquitin Specific Protease 8 (Usp8)mentioning

confidence: 99%

Genetics of Cushing's disease

Simon

Theodoropoulou

2022

J Neuroendocrinology

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P720R USP8 Mutation Is Associated with a Better Responsiveness to Pasireotide in ACTH-Secreting PitNETs

Treppiedi

Marra

Muro

et al. 2022

Cancers

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Somatic mutations in the ubiquitin specific peptidase 8 (USP8) gene have been associated with higher levels of somatostatin (SS) receptor subtype 5 (SSTR5) in adrenocorticotroph hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs). However, a correlation between the USP8 mutational status and favourable responses to pasireotide, the somatostatin multi-receptor ligand acting especially on SSTR5, has not been investigated yet. Here, we studied the impact of USP8 mutations on pasireotide responsiveness in human and murine corticotroph tumor cells. SSTR5 upregulation was observed in USP8 wild-type primary tumor cells transfected with S718del USP8 mutant. However, cell transfection with S718del USP8 and C40-USP8 mutants in in vitro sensitive cultures from USP8 wild-type tumors abolished their ability to respond to pasireotide and did not confer pasireotide responsiveness to the in vitro resistant culture. Pasireotide failed to reduce ACTH secretion in primary cells from one S718P USP8-mutated tumor but exerted a strong antisecretory effect in primary cells from one P720R USP8-mutated tumor. In agreement, AtT-20 cells transfection with USP8 mutants led to SSTR5 expression increase but pasireotide could reduce ACTH production and cyclin E expression in P720R USP8 overexpressing cells, only. In situ Proximity Ligation Assay and immunoflurescence experiments revealed that P720R USP8 mutant is still able to bind 14-3-3 proteins in AtT-20 cells, without affecting SSTR5 localization. In conclusion, P720R USP8 mutation might be considered as a molecular predictor of favourable response to pasireotide in corticotroph tumor cells.

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The molecular basis of ubiquitin-specific protease 8 autoinhibition by the WW-like domain

Cited by 2 publications

References 61 publications

Genetics of Cushing's disease

Genetics of Cushing's disease

P720R USP8 Mutation Is Associated with a Better Responsiveness to Pasireotide in ACTH-Secreting PitNETs

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