Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

Snyder, Joshua C.; Rochelle, Lauren K.; Marion, Sébastien; Lyerly, H. Kim; Barak, Larry S.; Caron, Marc G.

doi:10.1242/dev.124115

Cited by 4 publications

(5 citation statements)

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“…Furthermore, our results implicating Lgr4 in invasion/metastasis, potentially through regulation of EMT, are supported by similar roles in prostate (33, 77) and other cancers (32, 35). Our data suggesting regulation of actin dynamics through control of FAK/Src signaling, similar to the findings of Snyder and coworkers (78), opens a new area of Lgr4 function in need of further research.…”

Section: Discussionsupporting

confidence: 90%

“…EMT has been proposed as a crucial process in tumor metastasis. Both cells at the tumor invasive front and circulating breast tumor cells express EMT markers (77, 78), and inhibition of EMT impairs metastasis in mouse models (81). Among the transcription factors potentially driving EMT in breast cancer, we observed a significant decrease in SLUG and ZEB1 expression after LGR4 knockdown in vitro.…”

Section: Discussionmentioning

confidence: 99%

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LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells

Yue

Zeng

et al. 2017

FASEB j.

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The fourth member of the leucine-rich repeat-containing GPCR family (LGR4, frequently referred to as GPR48) and its cognate ligands, R-spondins (RSPOs) play crucial roles in the development of multiple organs as well as the survival of adult stem cells by activation of canonical Wnt signaling. Wnt/β-catenin signaling acts to regulate breast cancer; however, the molecular mechanisms determining its spatiotemporal regulation are largely unknown. In this study, we identified LGR4 as a master controller of Wnt/β-catenin signaling-mediated breast cancer tumorigenesis, metastasis, and cancer stem cell (CSC) maintenance. LGR4 expression in breast tumors correlated with poor prognosis. Either Lgr4 haploinsufficiency or mammary-specific deletion inhibited mouse mammary tumor virus (MMTV)- PyMT- and MMTV- Wnt1-driven mammary tumorigenesis and metastasis. Moreover, LGR4 down-regulation decreased in vitro migration and in vivo xenograft tumor growth and lung metastasis. Furthermore, Lgr4 deletion in MMTV- Wnt1 tumor cells or knockdown in human breast cancer cells decreased the number of functional CSCs by ∼90%. Canonical Wnt signaling was impaired in LGR4-deficient breast cancer cells, and LGR4 knockdown resulted in increased E-cadherin and decreased expression of N-cadherin and snail transcription factor -2 ( SNAI2) (also called SLUG), implicating LGR4 in regulation of epithelial-mesenchymal transition. Our findings support a crucial role of the Wnt signaling component LGR4 in breast cancer initiation, metastasis, and breast CSCs.-Yue, Z., Yuan, Z., Zeng, L., Wang, Y., Lai, L., Li, J., Sun, P., Xue, X., Qi, J., Yang, Z., Zheng, Y., Fang, Y., Li, D., Siwko, S., Li, Y., Luo, J., Liu, M. LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells

Yue

Zeng

et al. 2017

FASEB j.

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“…Forced retention of LGR5 245 at the cell surface induces a marked increase in the number of signaling filopodia on cells, (Carmon et al 2012;Snyder et al 2013;Snyder et al 2015). We confirmed that co- …”

Section: Lgr5-induced Filopodia As Wnt Signaling Platformssupporting

confidence: 72%

Visualizing Wnt secretion from Endoplasmic Reticulum to Filopodia

Moti

Boncompain

et al. 2018

Preprint

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Wnts are a family of secreted palmitoleated glycoproteins that play a key role in cell to cell communications during development and regulate stem cell compartments in adults. Wnt 20 receptors, downstream signaling cascades and target pathways have been extensively studied while less is known about how Wnts are secreted and move from producing cells to receiving cells. We used the synchronization system called Retention Using Selective Hook (RUSH) to study Wnt trafficking from endoplasmic reticulum to Golgi and then to plasma membrane and filopodia in real time. Consistent with prior studies, inhibition of porcupine (PORCN) or 25 knockout of Wntless (WLS) blocked Wnt exit from the ER. Indeed, WLS was rate-limiting for Wnt ER exit. Wnt-containing vesicles paused at sub-cortical regions of the plasma membrane before exiting the cell. Wnt-containing vesicles were transported to adjacent cells associated with filopodia. Increasing the number of filopodia by expression of LGR5 in the producing cell increased the ability of a cell to send a Wnt signal. The RUSH system is a 30 powerful tool to provide new insights into the Wnt secretory pathway.

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“…However, we found that inhibition of the mTOR pathway with rapamycin had no effect on the generation of protrusions in response to LPPR expression, although the amount of phosphorylated S6 ribosomal protein was vastly reduced. Most recently, thin fragile actin-rich membrane protrusions (termed 'cytonemes') have been produced in cells in response to the overexpression of the seven-transmembrane domain molecules Lgr4 and Lgr5 (Snyder et al, 2015). Lgr-induced protrusions share many common features with those we describe here, including being dependent upon membrane localization, sensitivity to actindepolymerization and being terminated by myosin X. Cytonemes have been identified as organizers of signaling molecules (Roy et al, 2014) and it might be that the activation of the mTOR pathway is a result of, rather than a cause of, protrusion formation.…”

Section: Discussionmentioning

confidence: 99%

Cooperative interactions of LPPR/PRG family members in membrane localization and alteration of cellular morphology

Agbaegbu

Malide²,

et al. 2015

Journal of Cell Science

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The lipid phosphate phosphatase-related proteins (LPPRs), also known as plasticity-related genes (PRGs), are classified as a new brain-enriched subclass of the lipid phosphate phosphatase (LPP) superfamily. They induce membrane protrusions, neurite outgrowth or dendritic spine formation in cell lines and primary neurons. However, the exact roles of LPPRs and the mechanisms underlying their effects are not certain. Here, we present the results of a large-scale proteome analysis to determine LPPR1-interacting proteins using coimmunoprecipitation coupled to mass spectrometry. We identified putative LPPR1-binding proteins involved in various biological processes. Most interestingly, we identified the interaction of LPPR1 with its family member LPPR3, LPPR4 and LPPR5. Their interactions were characterized by co-immunoprecipitation and colocalization analysis using confocal and super-resolution microscopy. Moreover, co-expressing two LPPR members mutually elevated their protein levels, facilitated their plasma membrane localization and resulted in an increased induction of membrane protrusions as well as the phosphorylation of S6 ribosomal protein. Taken together, we revealed a new functional cooperation between LPPR family members and discovered for the first time that LPPRs likely exert their function through forming complex with its family members.

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Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

Cited by 4 publications

References 1 publication

LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells

LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells

Visualizing Wnt secretion from Endoplasmic Reticulum to Filopodia

Cooperative interactions of LPPR/PRG family members in membrane localization and alteration of cellular morphology

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