Two Distinct Sites in Sonic Hedgehog Combine for Heparan Sulfate Interactions and Cell Signaling Functions

Chang, Shu Chun; Mulloy, Barbara; Magee, Anthony I.; Couchman, John R.

doi:10.1074/jbc.m111.285361

Cited by 61 publications

(80 citation statements)

References 41 publications

(51 reference statements)

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“…However, in Drosophila, when expressed in the Hh-receiving field, Sulf1 does not stimulate Hh signaling, but, on the contrary, reduces the response to the morphogen (Wojcinski et al, 2011). Accordingly, loss of Shh-HSPG interaction has been reported to reduce Shh signaling potency in vitro (Chang et al, 2011). These data, together with our present results showing that Sulf1 invariably activates Shh signaling in the neural tube, argue against Sulf1 acting in the immediate environment of Shh-receiving cells.…”

Section: Sulf1 Is Required Over Time For Neural Patterning Establishmsupporting

confidence: 72%

“…Furthermore, our data unambiguously show that MFP or LFP formation is not sufficient per se to activate expression of high Hh responsive genes at the correct time; instead Hh-expressing cells must express sulf1 to reach their full inductive potential. Shh is well known to interact with heparan sulfate (HS) chains and to preferentially bind HS chains having a high level of sulfation (Carrasco et al, 2005;Chang et al, 2011;Dierker et al, 2009;Farshi et al, 2011;Zhang et al, 2007). Therefore, as reported for other signaling molecules (Ai et al, 2003;Freeman et al, 2008;Viviano et al, 2004), Sulf1 activity is likely to lower Shh-HSPG interaction.…”

Section: Sulf1 Is Required Over Time For Neural Patterning Establishmmentioning

confidence: 99%

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Dynamics of Sonic hedgehog signaling in the ventral spinal cord are controlled by intrinsic changes in source cells requiring Sulfatase 1

et al. 2014

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In the ventral spinal cord, generation of neuronal and glial cell subtypes is controlled by Sonic hedgehog (Shh). This morphogen contributes to cell diversity by regulating spatial and temporal sequences of gene expression during development. Here, we report that establishing Shh source cells is not sufficient to induce the highthreshold response required to specify sequential generation of ventral interneurons and oligodendroglial cells at the right time and place in zebrafish. Instead, we show that Shh-producing cells must repeatedly upregulate the secreted enzyme Sulfatase1 (Sulf1) at two critical time points of development to reach their full inductive capacity. We provide evidence that Sulf1 triggers Shh signaling activity to establish and, later on, modify the spatial arrangement of gene expression in ventral neural progenitors. We further present arguments in favor of Sulf1 controlling Shh temporal activity by stimulating production of active forms of Shh from its source. Our work, by pointing out the key role of Sulf1 in regulating Shhdependent neural cell diversity, highlights a novel level of regulation, which involves temporal evolution of Shh source properties.

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Section: Sulf1 Is Required Over Time For Neural Patterning Establishmsupporting

confidence: 72%

Section: Sulf1 Is Required Over Time For Neural Patterning Establishmmentioning

confidence: 99%

Dynamics of Sonic hedgehog signaling in the ventral spinal cord are controlled by intrinsic changes in source cells requiring Sulfatase 1

et al. 2014

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“…Heparan sulfate and heparin binding of various morphogens, cytokines, chemokines, growth factors, proteases and protease inhibitors is mediated by clusters of basic amino acids on their surfaces. In vertebrate Hh proteins, heparan sulfate is mainly bound by the Cardin-Weintraub motif BBBxxBB (B represents a basic amino acid, x represents any amino acid) (Cardin and Weintraub, 1989;Chang et al, 2011;Farshi et al, 2011;Rubin et al, 2002), but Cardin-Weintraub residues also constitute the Nterminal Hh sheddase cleavage site (Ohlig et al, 2012). This suggests a possible mode of processing regulation by competitive heparan sulfate binding, consistent with recently described HSPG bioactivities in Hh-producing cells (Ayers et al, 2010;Bilioni et al, 2013;Oustah et al, 2014;Wojcinski et al, 2011).…”

Section: Introductionsupporting

confidence: 48%

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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“…Thus, we confirmed that Nterminally processed clusters are significantly more active than comparable amounts of largely unprocessed proteins. Note that the N-terminal CW sheddase target site also represents the binding site for heparan sulfate proteoglycans on the surface of Shh-producing cells (Chang et al, 2011;Farshi et al, 2011;Vyas et al, 2008); this suggests a possible mode of regulation of Shh release.…”

Section: Sheddases Release Dual-lipidated Shhnp From Producing Cellsmentioning

confidence: 99%

Scube2 enhances proteolytic Shh processing from the surface of Shh-producing cells

Jakobs

Exner

Schürmann

et al. 2014

Journal of Cell Science

112

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All morphogens of the Hedgehog (Hh) family are synthesized as dual-lipidated proteins, which results in their firm attachment to the surface of the cell in which they were produced. Thus, Hh release into the extracellular space requires accessory protein activities. We suggested previously that the proteolytic removal of N-and Cterminal lipidated peptides (shedding) could be one such activity. More recently, the secreted glycoprotein Scube2 (signal peptide, cubulin domain, epidermal-growth-factor-like protein 2) was also implicated in the release of Shh from the cell membrane. This activity strictly depended on the CUB domains of Scube2, which derive their name from the complement serine proteases and from bone morphogenetic protein-1/tolloid metalloproteinases (C1r/C1s, Uegf and Bmp1). CUB domains function as regulators of proteolytic activity in these proteins. This suggested that sheddases and Scube2 might cooperate in Shh release. Here, we confirm that sheddases and Scube2 act cooperatively to increase the pool of soluble bioactive Shh, and that Scube2-dependent morphogen release is unequivocally linked to the proteolytic processing of lipidated Shh termini, resulting in truncated soluble Shh. Thus, Scube2 proteins act as protease enhancers in this setting, revealing newly identified Scube2 functions in Hh signaling regulation.

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Two Distinct Sites in Sonic Hedgehog Combine for Heparan Sulfate Interactions and Cell Signaling Functions

Cited by 61 publications

References 41 publications

Dynamics of Sonic hedgehog signaling in the ventral spinal cord are controlled by intrinsic changes in source cells requiring Sulfatase 1

Dynamics of Sonic hedgehog signaling in the ventral spinal cord are controlled by intrinsic changes in source cells requiring Sulfatase 1

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

Scube2 enhances proteolytic Shh processing from the surface of Shh-producing cells

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