Evidence for a role of vertebrate Disp1 in long-range Shh signaling

Etheridge, Letitiah; Crawford, Timothy Q.; Zhang, Shile; Roelink, Henk

doi:10.1242/dev.043547

Cited by 60 publications

(78 citation statements)

References 46 publications

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“…The subcellular localization of Disp, and its function in the basolateral release of Hh, is in agreement with a recent report in vertebrates (48). The cellular phenotype of the loss of Disp function, such as the increase in the amount of Hh found in endocytic vesicles, which are supernumerary and disorganized, can be interpreted as a failure in Hh trafficking that subsequently affects its proper release.…”

Section: Discussionsupporting

confidence: 91%

Dispatched mediates Hedgehog basolateral release to form the long-range morphogenetic gradient in the Drosophila wing disk epithelium

Callejo

Bilioni

Mollica

et al. 2011

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

162

337

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Hedgehog (Hh) moves from the producing cells to regulate the growth and development of distant cells in a variety of tissues. Here, we have investigated the mechanism of Hh release from the producing cells to form a morphogenetic gradient in the Drosophila wing imaginal disk epithelium. We describe that Hh reaches both apical and basolateral plasma membranes, but the apical Hh is subsequently internalized in the producing cells and routed to the basolateral surface, where Hh is released to form a longrange gradient. Functional analysis of the 12-transmembrane protein Dispatched, the glypican Dally-like (Dlp) protein, and the Iglike and FNNIII domains of protein Interference Hh (Ihog) revealed that Dispatched could be involved in the regulation of vesicular trafficking necessary for basolateral release of Hh, Dlp, and Ihog. We also show that Dlp is needed in Hh-producing cells to allow for Hh release and that Ihog, which has been previously described as an Hh coreceptor, anchors Hh to the basolateral part of the disk epithelium.

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Section: Discussionsupporting

confidence: 91%

Dispatched mediates Hedgehog basolateral release to form the long-range morphogenetic gradient in the Drosophila wing disk epithelium

Callejo

Bilioni

Mollica

et al. 2011

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

162

337

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“…This finding is supported by the observed absence of (N-terminal) Shh processing in heparan sulfate-deficient cells and the potentiation of Shh processing by exogenous heparan sulfate in vitro. Hh sheddase activation by heparan sulfate is further consistent with the known increase of Hh solubilization by Suramine, a polysulfated compound (Etheridge et al, 2010) and with Syndecan 2 (another cell surface HSPG) acting as a docking receptor and activator for MMP7 (Ryu et al, 2009). Moreover, ADAM12 associates with HSPGs through its cysteine-rich domain (Iba et al, 2000), and heparan sulfate binding to ADAM12 transiently activates the enzyme (Sorensen et al, 2008).…”

Section: Discussionsupporting

confidence: 77%

Sonic hedgehog processing and release are regulated by glypican heparan sulfate proteoglycans

Ortmann,

Pickhinke,

Exner

et al. 2015

Journal of Cell Science

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There was an error published in J. Cell Sci. 128, 2374-2385.The reference Oustah et al. (2014) was cited incorrectly throughout the manuscript and in the reference list. Citations of Oustah et al. (2014) should read Al Oustah et al. (2014), and the correct reference is given below.Al Oustah, A., Danesin, C., Khouri-Farah, N., Farreny, M.-A., Escalas, N., Cochard, P., Glise, B. and Soula, C. (2014 show that glypican heparan sulfate proteoglycans regulate this process, through their heparan sulfate chains, in a cell autonomous manner. Heparan sulfate specifically modifies Shh processing at the cell surface, and purified glycosaminoglycans enhance the proteolytic removal of N-and C-terminal Shh peptides under cellfree conditions. The most likely explanation for these observations is direct Shh processing in the extracellular compartment, suggesting that heparan sulfate acts as a scaffold or activator for Shh ligands and the factors required for their turnover. We also show that purified heparan sulfate isolated from specific cell types and tissues mediates the release of bioactive Shh from pancreatic cancer cells, revealing a previously unknown regulatory role for these versatile molecules in a pathological context.

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“…This protein (D99Y) was unable to rescue the effect of ADAM silencing, and in fact was found to result in increased Hh levels in control silenced cells. This is probably a consequence of the dominantnegative action such a mutant molecule could have in the previously described trimers that DISP1 functions in (see Etheridge et al, 2010). These results show that the fraction of Hh that accumulates on the cell surface in the absence of ADAM17 can still be transferred by DISP1 to some other machinery that disperses Hh from the cell surface.…”

Section: Expression Of Adams In Pancreatic Cancers Patient-derived Xmentioning

confidence: 64%

“…A positive control for the effects of a blocked Hh release came from the knockdown of DISP1. Although the exact working mechanism of this protein is not fully understood, its involvement in the spread of lipid-modified Hh from mammalian cells is well established (Ayers et al, 2010;Caspary et al, 2002;Ma et al, 2002;Etheridge et al, 2010) and indeed, knockdown of DISP1 led to an increase in surface levels of Hh as measured by immunofluorescence staining (Fig. 4A) and flow cytometry (Fig.…”

Section: Expression Of Adams In Pancreatic Cancers Patient-derived Xmentioning

confidence: 98%

Blocking Hedgehog release from pancreatic cancer cells increases paracrine signaling potency

Damhofer

Veenstra

Tol

et al. 2014

Journal of Cell Science

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Members of the Hedgehog (Hh) family of morphogens play crucial roles in development but are also involved in the progression of certain types of cancer. Despite being synthesized as hydrophobic dually lipid-modified molecules, and thus being strongly membraneassociated, Hh ligands are able to spread through tissues and act on target cells several cell diameters away. Various mechanisms that mediate Hh release have been discussed in recent years; however, little is known about dispersion of this ligand from cancer cells. Using co-culture models in conjunction with a newly developed reporter system, we were able to show that different members of the ADAM family of metalloproteinases strongly contribute to the release of endogenous bioactive Hh from pancreatic cancer cells, but that this solubilization decreases the potency of cancer cells to signal to adjacent stromal cells in direct co-culture models. These findings imply that under certain conditions, cancer-cell-tethered Hh molecules are the more potent signaling activators and that retaining Hh on the surface of cancer cells can unexpectedly increase the effective signaling range of this ligand, depending on tissue context.

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Evidence for a role of vertebrate Disp1 in long-range Shh signaling

Cited by 60 publications

References 46 publications

Dispatched mediates Hedgehog basolateral release to form the long-range morphogenetic gradient in the Drosophila wing disk epithelium

Dispatched mediates Hedgehog basolateral release to form the long-range morphogenetic gradient in the Drosophila wing disk epithelium

Sonic hedgehog processing and release are regulated by glypican heparan sulfate proteoglycans

Blocking Hedgehog release from pancreatic cancer cells increases paracrine signaling potency

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