PTPN2 copper-sensing relays copper level fluctuations into EGFR/CREB activation and associated CTR1 transcriptional repression.

Autor: Ross MO; Department of Chemistry, University of Chicago, Chicago, IL, USA. matthewross@uchicago.edu., Xie Y; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA., Owyang RC; Department of Chemistry, University of Chicago, Chicago, IL, USA., Ye C; Department of Chemistry, University of Chicago, Chicago, IL, USA., Zbihley ONP; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA., Lyu R; Department of Chemistry, University of Chicago, Chicago, IL, USA., Wu T; Department of Chemistry, University of Chicago, Chicago, IL, USA., Wang P; Department of Chemistry, University of Chicago, Chicago, IL, USA., Karginova O; Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, IL, USA., Olopade OI; Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, IL, USA., Zhao M; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA., He C; Department of Chemistry, University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.; Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 13; Vol. 15 (1), pp. 6947. Date of Electronic Publication: 2024 Aug 13.
DOI: 10.1038/s41467-024-50524-5
Abstrakt: Fluxes in human copper levels recently garnered attention for roles in cellular signaling, including affecting levels of the signaling molecule cyclic adenosine monophosphate. We herein apply an unbiased temporal evaluation of the signaling and whole genome transcriptional activities modulated by copper level fluctuations to identify potential copper sensor proteins responsible for driving these activities. We find that fluctuations in physiologically relevant copper levels modulate EGFR signal transduction and activation of the transcription factor CREB. Both intracellular and extracellular assays support Cu 1+  inhibition of the EGFR phosphatase PTPN2 (and potentially PTPN1)-via ligation to the PTPN2 active site cysteine side chain-as the underlying mechanism. We additionally show i) copper supplementation drives weak transcriptional repression of the copper importer CTR1 and ii) CREB activity is inversely correlated with CTR1 expression. In summary, our study reveals PTPN2 as a physiological copper sensor and defines a regulatory mechanism linking feedback control of copper stimulated EGFR/CREB signaling and CTR1 expression.
(© 2024. The Author(s).)
Databáze: MEDLINE
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