期刊
CELL REPORTS
卷 28, 期 6, 页码 1511-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.07.023
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- Taiwan Ministry of Science and Technology [105-2320-B-007-004-MY3]
Secreted frizzled-related proteins (SFRPs) are mainly known for their role as extracellular modulators and tumor suppressors that downregulate Wnt signaling. Using the established (CRISPR/Cas9 targeting promoters of SFRPs and targeting SFRPs transcript) system, we find that nuclear SFRPs interact with beta-catenin and either promote or suppress TCF4 recruitment. SFRPs bind with beta-catenin on both their N and C termini, which the repressive effects caused by SFRP-beta-catenin-N-terminus binding overpower the promoting effects of their binding at the C terminus. By high Wnt activity, beta-catenin and SFRPs only bind with their C termini, which results in the upregulation of beta-catenin transcriptional activity and cancer stem cell (CSC)-related genes. Furthermore, we identify disulfide bonds of the cysteine-rich domain (CRD) and two threonine phosphorylation events of the netrin-related motif (NTR) domain of SFRPs that are essential for their role as biphasic modulators, suggesting that SFRPs are biphasic modulators of Wnt signaling-elicited CSC properties beyond extracellular control.
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