Trans-Synaptic Transmission of Vesicular Wnt Signals through Evi/Wntless

Korkut, Ceren; Ataman, Bulent; Ramachandran, Preethi; Ashley, James A.; Barría, Romina; Gherbesi, Norberto G.; Budnik, Vivian

doi:10.1016/j.cell.2009.07.051

Cited by 401 publications

(457 citation statements)

References 42 publications

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“…In the wing disc the primary role of Dally and Dally-like protein is not to transduce the Wg signal but to stabilize the protein in the extracellular space (42,45). In the larval neuromuscular junction, there is evidence that Wg travels between cells on exosome-like vesicles containing the Wnt-binding transmembrane protein Evenness Interrupted/ Wntless/Sprinter (46). Lipoprotein particles composed of Lipophorin also play a role in the transport of two lipid-linked morphogens, Wg and Hh (18).…”

Section: Discussionmentioning

confidence: 99%

Secreted Wingless-interacting molecule (Swim) promotes long-range signaling by maintaining Wingless solubility

Mulligan

Fuerer

Ching

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

164

142

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Lipid-modified Wnt/Wingless (Wg) proteins can signal to their target cells in a short- or long-range manner. How these hydrophobic proteins travel through the extracellular environment remains an outstanding question. Here, we report on a Wg binding protein, Secreted Wg-interacting molecule (Swim), that facilitates Wg diffusion through the extracellular matrix. Swim, a putative member of the Lipocalin family of extracellular transport proteins, binds to Wg with nanomolar affinity in a lipid-dependent manner. In quantitative signaling assays, Swim is sufficient to maintain the solubility and activity of purified Wg. In Drosophila , swim RNAi phenotypes resemble wg loss-of-function phenotypes in long-range signaling. We propose that Swim is a cofactor that promotes long-range Wg signaling in vivo by maintaining the solubility of Wg.

show abstract

Section: Discussionmentioning

confidence: 99%

Secreted Wingless-interacting molecule (Swim) promotes long-range signaling by maintaining Wingless solubility

Mulligan

Fuerer

Ching

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

164

142

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“…Since Wnt proteins/morphogens are insolu-ble and highly lipophilic, they require a specialized transport system. One way to transport Wnt proteins are lipoprotein particles, which associate with lipid modified Wnts [197,198]. Another interesting way to transport Wnts is a direct translocation from cell to cell through a series of exocytosis-endocytosis cycles [199].…”

Section: The Wnt Receptor Complexmentioning

confidence: 99%

“…Another interesting way to transport Wnts is a direct translocation from cell to cell through a series of exocytosis-endocytosis cycles [199]. Hence, Wnts can be transported between the cells via exosomal vesicles [198,200].…”

Section: The Wnt Receptor Complexmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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“…This suggests that endosome-to-TGN trafficking via the retromer pathway can result in accumulation of internalized GPRC5B proteins at the TGN prior to exosomal release. Retromer-dependent trafficking to the TGN compartment could account for secretion of other exosome cargos, such as the Wnt-releasing factor Wntless (Wls; also known as Evi) (6,53). Wls was shown to move from the plasma membrane to the TGN via the retromer pathway (5, 6, 54 -58).…”

Section: Discussionmentioning

confidence: 99%

Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex

Kwon

Nacke

et al. 2016

Journal of Biological Chemistry

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Edited by Thomas SöllnerExosomes, 40 -150-nm extracellular vesicles, transport biological macromolecules that mediate intercellular communications. Although exosomes are known to originate from maturation of endosomes into multivesicular endosomes (also known as multivesicular bodies) with subsequent fusion of the multivesicular endosomes with the plasma membrane, it remains unclear how cargos are selected for exosomal release. Using an inducible expression system for the exosome cargo protein GPRC5B and following its trafficking trajectory, we show here that newly synthesized GPRC5B protein accumulates in the Golgi complex prior to its release into exosomes. The L-type lectin LMAN2 (also known as VIP36) appears to be specifically required for the accumulation of GPRC5B in the Golgi complex and restriction of GPRC5B transport along the exosomal pathway. This may occur due to interference with the adaptor protein GGA1-mediated trans Golgi network-to-endosome transport of GPRC5B. The adaptor protein CD2AP-mediated internalization following cell surface delivery appears to contribute to the Golgi accumulation of GPRC5B, possibly in parallel with biosynthetic/secretory trafficking from the endoplasmic reticulum. Our data thus reveal a Golgi-traversing pathway for exosomal release of the cargo protein GPRC5B in which CD2AP facilitates the entry and LMAN2 impedes the exit of the flux, respectively.

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Trans-Synaptic Transmission of Vesicular Wnt Signals through Evi/Wntless

Cited by 401 publications

References 42 publications

Secreted Wingless-interacting molecule (Swim) promotes long-range signaling by maintaining Wingless solubility

Secreted Wingless-interacting molecule (Swim) promotes long-range signaling by maintaining Wingless solubility

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex

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