Deubiquitinating enzymes USP4 and USP17 finetune the trafficking of PDGFRß and affect PDGF-BB-induced STAT3 signalling.
Cell Mol Life Sci
; 79(2): 85, 2022 Jan 21.
Article
em En
| MEDLINE
| ID: mdl-35064336
Interaction of platelet-derived growth factor (PDGF) isoforms with their receptors results in activation and internalization of receptors, with a concomitant activation of downstream signalling pathways. Ubiquitination of PDGFRs serves as a mark to direct the internalization and sorting of the receptors. By overexpressing a panel of deubiquitinating enzymes (DUBs), we found that USP17 and USP4 efficiently deubiquitinate PDGF receptor ß (PDGFRß) and are able to remove both Lys63 and Lys48-linked polyubiquitin chains from the receptor. Deubiquitination of PDGFRß did not affect its stability, but regulated the timing of its trafficking, whereby USP17 prolonged the presence of the receptor at the cell surface, while USP4 affected the speed of trafficking towards early endosomes. Induction of each of the DUBs in BJhTERT fibroblasts and U2OS osteosarcoma cells led to prolonged and/or shifted activation of STAT3 in response to PDGF-BB stimulation, which in turn led to increased transcriptional activity of STAT3. Induction of USP17 promoted acute upregulation of the mRNA expression of STAT3-inducible genes STAT3, CSF1, junB and c-myc, while causing long-term changes in the expression of myc and CDKN1A. Deletion of USP17 was lethal to fibroblasts, while deletion of USP4 led to a decreased proliferative response to stimulation by PDGF-BB. Thus, USP17- and USP4-mediated changes in ubiquitination of PDFGRß lead to dysregulated signalling and transcription downstream of STAT3, resulting in defects in the control of cell proliferation.
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MEDLINE
Assunto principal:
Endopeptidases
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Transdução de Sinais
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Receptor beta de Fator de Crescimento Derivado de Plaquetas
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Fator de Transcrição STAT3
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Proteases Específicas de Ubiquitina
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Becaplermina
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article