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http://purl.uniprot.org/citations/30409180http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/30409180http://www.w3.org/2000/01/rdf-schema#comment"

Background

The deubiquitinase USP17 is overexpressed in NSCLC and has been shown to be required for the growth and motility of EGFR wild-type (WT) NSCLC cells. USP17 is also required for clathrin-mediated endocytosis of EGFR. Here, we examine the impact of USP17 depletion on the growth, as well as EGFR endocytosis and signaling, of EGFR mutant (MT) NSCLC cells. In particular, we examine NSCLC cells harboring an EGFR activating exon 19 deletion (HCC827), or both the L858R activating mutation and the T790M resistance gatekeeper mutation (H1975) which renders them resistant to EGFR tyrosine kinase inhibitors (TKIs).

Methods

MTT, trypan blue and clonogenic assays, confocal microscopy, Western blotting and cell cycle analysis were performed.

Results

USP17 depletion blocks the growth of EGFRMT NSCLC cells carrying either the EGFR exon 19 deletion, or L858R/T790M double mutation. In contrast to EGFRWT cells, USP17 depletion also triggers apoptosis of EGFRMT NSCLC cells. USP17 is required for clathrin-mediated endocytosis in these EGFRMT NSCLC cells, but it is not required for the internalization of the mutated EGFR receptors. Instead, USP17 depletion alters the localization of these receptors within the cell, and although it does not decrease basal EGFR activation, it potently reduces activation of Src, a key kinase in mutant EGFR-dependent tumorigenicity. Finally, we demonstrate that USP17 depletion can trigger apoptosis in EGFRWT NSCLC cells, when combined with the EGFR tyrosine kinase inhibitor (TKI) gefitinib.

Conclusions

Our data reveals that USP17 facilitates trafficking and oncogenic signaling of mutant EGFR and indicates targeting USP17 could represent a viable therapeutic strategy in NSCLC tumours carrying either an EGFR activating mutation, or a resistance gatekeeper mutation."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.org/dc/terms/identifier"doi:10.1186/s12964-018-0291-5"xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"Jiang L."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"Lin J."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"Burrows J.F."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"Evergren E."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"Burden R.E."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"Scott C.J."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"Smyth P."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"Van Schaeybroeck S."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"Cogo F."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"McCann A.P."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/author"McDaid W.J."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/date"2018"xsd:gYear
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/name"Cell Commun Signal"xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/pages"77"xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/title"USP17 is required for trafficking and oncogenic signaling of mutant EGFR in NSCLC cells."xsd:string
http://purl.uniprot.org/citations/30409180http://purl.uniprot.org/core/volume"16"xsd:string
http://purl.uniprot.org/citations/30409180http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/30409180
http://purl.uniprot.org/citations/30409180http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/30409180
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