Follistatin-like 1 (FSTL1) interacts with Wnt ligands and Frizzled receptors to enhance Wnt/β-catenin signaling in obstructed kidneys in vivo
Follistatin (FS)-like 1 (FSTL1) is a member of the FS-SPARC (secreted protein, acidic and rich in cysteine) family of secreted and extracellular matrix proteins. The functions of FSTL1 have been studied in heart and lung injury as well as in wound healing; however, the role of FSTL1 in the kidney is...
Main Authors: | , , , , , , , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
Published: |
American Society for Biochemistry and Molecular Biology Inc.
2022
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Subjects: | |
Online Access: | View Fulltext in Publisher |
LEADER | 03381nam a2200589Ia 4500 | ||
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001 | 10.1016-j.jbc.2022.102010 | ||
008 | 220706s2022 CNT 000 0 und d | ||
020 | |a 00219258 (ISSN) | ||
245 | 1 | 0 | |a Follistatin-like 1 (FSTL1) interacts with Wnt ligands and Frizzled receptors to enhance Wnt/β-catenin signaling in obstructed kidneys in vivo |
260 | 0 | |b American Society for Biochemistry and Molecular Biology Inc. |c 2022 | |
856 | |z View Fulltext in Publisher |u https://doi.org/10.1016/j.jbc.2022.102010 | ||
520 | 3 | |a Follistatin (FS)-like 1 (FSTL1) is a member of the FS-SPARC (secreted protein, acidic and rich in cysteine) family of secreted and extracellular matrix proteins. The functions of FSTL1 have been studied in heart and lung injury as well as in wound healing; however, the role of FSTL1 in the kidney is largely unknown. Here, we show using single-cell RNA-Seq that Fstl1 was enriched in stromal cells in obstructed mouse kidneys. In addition, immunofluorescence demonstrated that FSTL1 expression was induced in fibroblasts during kidney fibrogenesis in mice and human patients. We demonstrate that FSTL1 overexpression increased renal fibrosis and activated the Wnt/β-catenin signaling pathway, known to promote kidney fibrosis, but not the transforming growth factor β (TGF-β), Notch, Hedgehog, or Yes-associated protein (YAP) signaling pathways in obstructed mouse kidneys, whereas inhibition of FSTL1 lowered Wnt/β-catenin signaling. Importantly, we show that FSTL1 interacted with Wnt ligands and the Frizzled (FZD) receptors but not the coreceptor lipoprotein receptor–related protein 6 (LRP6). Specifically, we found FSTL1 interacted with Wnt3a through its extracellular calcium–binding (EC) domain and von Willebrand factor type C–like (VWC) domain, and with FZD4 through its EC domain. Furthermore, we show that FSTL1 increased the association of Wnt3a with FZD4 and promoted Wnt/β-catenin signaling and fibrogenesis. The EC domain interacting with both Wnt3a and FZD4 also enhanced Wnt3a signaling. Therefore, we conclude that FSTL1 is a novel extracellular enhancer of the Wnt/β-catenin pathway. © 2022 The Authors | |
650 | 0 | 4 | |a Amino acids |
650 | 0 | 4 | |a Calcium-binding domain |
650 | 0 | 4 | |a Catenin signaling |
650 | 0 | 4 | |a Cell culture |
650 | 0 | 4 | |a Extracellular |
650 | 0 | 4 | |a Fibrogenesis |
650 | 0 | 4 | |a Follistatin-like 1 |
650 | 0 | 4 | |a Frizzled |
650 | 0 | 4 | |a FSTL1 |
650 | 0 | 4 | |a FZD |
650 | 0 | 4 | |a kidney fibrosis |
650 | 0 | 4 | |a Kidney fibrosis |
650 | 0 | 4 | |a Ligands |
650 | 0 | 4 | |a Mammals |
650 | 0 | 4 | |a Mouse kidney |
650 | 0 | 4 | |a Proteins |
650 | 0 | 4 | |a Signaling |
650 | 0 | 4 | |a Wnt |
650 | 0 | 4 | |a β-catenin |
700 | 1 | |a Dai, C. |e author | |
700 | 1 | |a Feng, B. |e author | |
700 | 1 | |a Hambrock, H.O. |e author | |
700 | 1 | |a Hartmann, U. |e author | |
700 | 1 | |a Huang, H. |e author | |
700 | 1 | |a Huang, Y. |e author | |
700 | 1 | |a Lan, H.-Y. |e author | |
700 | 1 | |a Li, J. |e author | |
700 | 1 | |a Liu, Y. |e author | |
700 | 1 | |a Liu, Y. |e author | |
700 | 1 | |a Mak, K.K. |e author | |
700 | 1 | |a Qin, J. |e author | |
700 | 1 | |a Wang, Y. |e author | |
700 | 1 | |a Xia, Y. |e author | |
700 | 1 | |a Xu, C. |e author | |
700 | 1 | |a Zeng, Y. |e author | |
700 | 1 | |a Zhang, X. |e author | |
700 | 1 | |a Zhang, Y. |e author | |
700 | 1 | |a Zheng, G. |e author | |
700 | 1 | |a Zheng, Z.-H. |e author | |
773 | |t Journal of Biological Chemistry |