Wnt traffic from endoplasmic reticulum to filopodia

Moti, Naushad; Yu, Jia; Boncompain, Gaëlle; Perez, Franck; Virshup, David M.

doi:10.1371/journal.pone.0212711

Cited by 25 publications

(17 citation statements)

References 46 publications

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“…In our experimental approach to study the effects of WNT2 on colon cancer angiogenesis, we only use direct cell-cell contact to assure proper induction of signaling, as WNT signaling in most cases is dependent on the direct contact of WNT-producing and responding cells [58,59]. Moreover, we avoid using recombinant WNT2 since we have previously shown that commercially available rhWNT2 was not able to induce canonical WNT signaling in reporter cells [24].…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer

et al. 2019

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WNT2 acts as a pro-angiogenic factor in placental vascularization and increases angiogenesis in liver sinusoidal endothelial cells (ECs) and other ECs. Increased WNT2 expression is detectable in many carcinomas and participates in tumor progression. In human colorectal cancer (CRC), WNT2 is selectively elevated in cancer-associated fibroblasts (CAFs), leading to increased invasion and metastasis. However, if there is a role for WNT2 in colon cancer, angiogenesis was not addressed so far. We demonstrate that WNT2 enhances EC migration/invasion, while it induces canonical WNT signaling in a small subset of cells. Knockdown of WNT2 in CAFs significantly reduced angiogenesis in a physiologically relevant assay, which allows precise assessment of key angiogenic properties. In line with these results, expression of WNT2 in otherwise WNT2-devoid skin fibroblasts led to increased angiogenesis. In CRC xenografts, WNT2 overexpression resulted in enhanced vessel density and tumor volume. Moreover, WNT2 expression correlates with vessel markers in human CRC. Secretome profiling of CAFs by mass spectrometry and cytokine arrays revealed that proteins associated with pro-angiogenic functions are elevated by WNT2. These included extracellular matrix molecules, ANG-2, IL-6, G-CSF, and PGF. The latter three increased angiogenesis. Thus, stromal-derived WNT2 elevates angiogenesis in CRC by shifting the balance towards pro-angiogenic signals.

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Section: Discussionmentioning

confidence: 99%

Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer

et al. 2019

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“…BiP, protein disulfide isomerases (PDI), GRP94), and ERAD 520 components -which are all represented in our list of interactors. We also found SEC62 521 to interact with proteins that function in the Wnt and Notch signaling pathways, which are 522 less commonly studied in the context of ER regulation, though it has been reported that 523 Wnt signaling proteins are retained in the ER due to inefficient secretion (Burrus and 524 McMahon, 1995;Moti et al, 2019). To this point, the ER-resident glycoprotein, Oto, 525 regulates Wnt activity by binding Wnt1 and Wnt3a to facilitate its retention in the ER 526 (Zoltewicz et al, 2009).…”

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confidence: 80%

Quantitative proteomics links the LRRC59 interactome to mRNA translation on the ER membrane

Hannigan

Hoffman

Thompson

et al. 2020

Preprint

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1 Hannigan et al. characterize the protein interactomes of four ER ribosome-binding 2 proteins, providing evidence that ER-bound ribosomes reside in distinct molecular 3 environments. Their data link SEC62 to ER redox regulation and chaperone trafficking, 4 and suggest a role for LRRC59 in SRP-coupled protein synthesis. 5 6 Abstract 7 Protein synthesis on the endoplasmic reticulum (ER) requires the dynamic coordination 8 of resident membrane proteins and cytoplasmic translation factors. While ER membrane 9 proteins functioning in ribosome association, mRNA anchoring, and protein translocation, 10 have been identified, little is known regarding the higher order organization of ER-11 localized translation. Here we utilized proximity proteomics to identify neighboring protein 12 networks for the ribosome interactors SEC61b, RPN1, SEC62, and LRRC59. Whereas 13 the SEC61b and RPN1 BioID reporters revealed translocon-associated networks, the 14 SEC62 and LRRC59 reporters identified divergent interactome networks of previously 15 unexplored functions. Notably, the SEC62 interactome is enriched in redox-linked 16 proteins and ER luminal chaperones, whereas the LRRC59 interactome is enriched in 17 SRP pathway components, translation factors, and ER-localized RNA-binding proteins.18

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“…Recent studies provide insights into the possible secretory pathways of Wnt proteins and adds further support for the idea that the WNT5A isoforms are differentially directed to either an autocrine or paracrine pathway. Moti et al 29 eloquently showed that Wnt‐containing secretory vesicles can associate with specialized, signaling filopodia called cytonemes, which deliver the Wnt‐containing vesicle to the receiving cell. Alternatively, the Wnt‐containing Golgi transport vesicle can fuse with the plasma membrane, releasing the Wnt ligand to act in an autocrine fashion.…”

Section: Discussionmentioning

confidence: 99%

The human WNT5A isoforms display similar patterns of expression but distinct and overlapping activities in normal human osteoblasts

Bhandari

Elshaarrawi

Katula

2021

J of Cellular Biochemistry

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WNT5A activates noncanonical Wnt signaling pathways and has critical functions in early development, differentiation, and tissue homeostasis. Two major WNT5A protein isoforms, which in this study we term WNT5A-L(A) and WNT5A-S(B), have been identified that differ by 18 AA at their amino terminus. Functional differences between the isoforms have been indicated in studies utilizing cancer cell lines but the activities of the isoforms in normal cells and during differentiation have not been explored. We examined the WNT5A isoforms in the normal osteoblast cell line hFOB1.19. WNT5A-L(A) and WNT5A-S(B) transcripts increased from Days 3 to 21 of differentiation but WNT5A-S(B) showed a greater fold-change. In undifferentiated cells, there are 2-fold more WNT5A-L(A) than WNT5A-S(B) transcripts. Total intracellular WNT5A protein increased up to 3-fold during differentiation. siRNA knockdown of total WNT5A leads to a decrease in the expression of the differentiation markers, osteocalcin and RUNX2. Conditioned medium containing the isoform proteins [CM-L(A) and CM-S(B)] was used to analyze the effects of the isoforms on β-catenin and noncanonical signaling, proliferation, gene expression, and alkaline phosphatase (ALP) activity. Treatment with both CM-L(A) and CM-S(B) reduced β-catenin signaling. CM-L(A) but not CM-S(B) significantly increased the proliferation of nondifferentiated hFOB1.19 cells. CM-L(A) enhanced osteocalcin transcripts over 2-fold in differentiating cells, whereas CM-S(B) had no effect. Analysis of differentiating cells up to Day 21 revealed no significant effect of treatment with CM-L(A) or CM-S(B) on ALP activity or osteocalcin gene expression. pJNK levels were unaffected in proliferating cells by treatment with neither isoform. pPKC increased slightly in CM-L(A)treated cells at 15 min but by 2 h pPKC levels were less than the control. CM-S(B)had a more robust effect on pPKC levels that continued up to 2 h. Together these This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Wnt traffic from endoplasmic reticulum to filopodia

Cited by 25 publications

References 46 publications

Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer

Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer

Quantitative proteomics links the LRRC59 interactome to mRNA translation on the ER membrane

The human WNT5A isoforms display similar patterns of expression but distinct and overlapping activities in normal human osteoblasts

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