DUSP6 regulates Notch1 signalling in colorectal cancer

Chin Wen Png, Madhushanee Weerasooriya, Heng Li, Xiaowen Hou, Fiona Yayuan Teo, Shiying Huang, Zheng Ser, Franklin Yau Kok Weng, Malini Rethnam, Gloryn Chia, Radoslaw M. Sobota, Choon Seng Chong, Ker-Kan Tan and Yongliang Zhang ()
Additional contact information
Chin Wen Png: National University of Singapore
Madhushanee Weerasooriya: National University of Singapore
Heng Li: National University of Singapore
Xiaowen Hou: National University of Singapore
Fiona Yayuan Teo: National University of Singapore
Shiying Huang: National University of Singapore
Zheng Ser: Technology and Research (A*STAR)
Franklin Yau Kok Weng: National University of Singapore
Malini Rethnam: National University of Singapore
Gloryn Chia: National University of Singapore
Radoslaw M. Sobota: Technology and Research (A*STAR)
Choon Seng Chong: National University of Singapore
Ker-Kan Tan: National University of Singapore
Yongliang Zhang: National University of Singapore

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Notch1 plays various roles in cancer development, and Notch1-induced transactivation is controlled by phosphorylation of its cleaved intracellular domain. However, it is unclear whether there are phosphatases capable of dephosphorylating the cleaved Notch1 transmembrane/intracellular region (NTM) to regulate its function. Here, we show that DUSP6 can function as a phosphatase for Notch1, thereby regulating NTM stability and transcriptional activity, thus influencing colorectal cancer (CRC) development. In human CRC cells, elevated DUSP6 expression correlates with increased NTM levels, leading to enhanced CRC cell proliferation both in vitro and in vivo. High tumoral DUSP6 protein expression is associated with poorer overall CRC patient survival. In mice, DUSP6 deficiency results in reduced CRC development. Mechanistically, DUSP6 dephosphorylates phospho-Y2116, which in turn reduces NTM ubiquitination, leading to increased NTM stability and transcriptional activity. As a result, the expression of Notch1-targeted proliferation genes is increased to promote tumour cell growth.

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

Downloads: (external link)
https://www.nature.com/articles/s41467-024-54383-y 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_s41467-024-54383-y

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

DOI: 10.1038/s41467-024-54383-y

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 ().