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

Matthew O. Ross (), Yuan Xie, Ryan C. Owyang, Chang Ye, Olivia N. P. Zbihley, Ruitu Lyu, Tong Wu, Pingluan Wang, Olga Karginova, Olufunmilayo I. Olopade, Minglei Zhao and Chuan He ()
Additional contact information
Matthew O. Ross: University of Chicago
Yuan Xie: University of Chicago
Ryan C. Owyang: University of Chicago
Chang Ye: University of Chicago
Olivia N. P. Zbihley: University of Chicago
Ruitu Lyu: University of Chicago
Tong Wu: University of Chicago
Pingluan Wang: University of Chicago
Olga Karginova: University of Chicago
Olufunmilayo I. Olopade: University of Chicago
Minglei Zhao: University of Chicago
Chuan He: University of Chicago

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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 Cu1+ 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-50524-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50524-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-50524-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().