DUSP6 regulates Notch1 signalling in colorectal cancer

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.

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Publication Details

Journal
Nature Communications
Published
2024-11-21
DOI
https://doi.org/10.1038/s41467-024-54383-y
Citations
10
Primary Topic
Protein Tyrosine Phosphatases
Type
article
Field-Weighted Citation Impact
2.34

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article

DUSP6 regulates Notch1 signalling in colorectal cancer

Malini Rethnam, Gloryn Chia, Choon Seng Chong, Chin Wen Png et al.
10 citations
Nature Communications
Protein Tyrosine Phosphatases
2.34
article

DUSP6 regulates Notch1 signalling in colorectal cancer

Malini Rethnam, Gloryn Chia, Choon Seng Chong, Chin Wen Png, Radoslaw M. Sobota, Fuzhong Weng, Ker‐Kan Tan, Zheng Ser, Xiaowen Hou, Madhushanee Weerasooriya, Heng Li, Yongliang Zhang, Shiying Huang, Fiona Yayuan Teo
article en
10 citations

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.

Nature CommunicationsVol. 15(1)
Agency for Science, Technology and Research (SG), National University of Singapore (SG), Singapore Institute of Technology (SG), Institute of Molecular and Cell Biology (SG)
National University Health System, Medical Research Council, National Medical Research Council
Good health and well-being
Openalex Percentile: Top 11%
Protein Tyrosine Phosphatases
2.34
DOIOpen Access PDFOpenAlex
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