Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses

Chan, Jennifer A.; Balasubramanian, Srividya; Witt, Rochelle M.; Nazemi, Kellie; Choi, Yoojin; Pazyra-Murphy, Maria F.; Walsh, C.T.; Thompson, Margaret A.; Segal, Rosalind A.

doi:10.1038/nn.2287

Cited by 72 publications

(88 citation statements)

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“…Much data have subsequently been compiled showing that this is only one of a number of cationic sequences that can bind glycosaminoglycans (38). The importance of the Lys-32-38 region in Shh for binding heparin and HS has been demonstrated (38). Our molecular modeling of murine Shh, however, suggested that another lysine residue 179 on the surface of Shh (Lys-178 in the human sequence) may also contribute to overall affinity of the morphogen for heparin.…”

Section: Discussionmentioning

confidence: 97%

“…This region (Lys-32-38) precisely coincides with a consensus sequence for heparin binding, known as the Cardin-Weintraub motif (23). Much data have subsequently been compiled showing that this is only one of a number of cationic sequences that can bind glycosaminoglycans (38). The importance of the Lys-32-38 region in Shh for binding heparin and HS has been demonstrated (38).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, given that the Cardin-Weintraub motif, although important, does not include the sole heparin-binding sequence of Shh, previous data can be re-evaluated. For example, work in mice has shown that a R34A/K38A mutation in Shh reduced (but did not ablate) proteoglycan affinity but did not alter Ptc affinity (38). Moreover, although the mutant Shh had reduced ability to promote proliferation, neuronal tissue patterning was not affected.…”

Section: Discussionmentioning

confidence: 99%

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

Chang

Mulloy

Magee

et al. 2011

Journal of Biological Chemistry

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Background:The morphogen, sonic hedgehog, has important roles in development and disease and is in part dependent on heparan sulfate interactions. Results: Two sites in the protein are shown to contribute to heparan sulfate interactions and biological activity. Conclusion: A new site in sonic hedgehog is identified that regulates its biological activity. Significance: The data provide new insight into the important role of proteoglycan interactions with sonic hedgehog.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Chang

Mulloy

Magee

et al. 2011

Journal of Biological Chemistry

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“…HS expression and Dally-like/glypican expression are also essential for signal reception and modulation on Ptc-expressing receiving cells (10 -14) and participate in HhNp-Ihog interaction (15). However, the essential role of direct morphogen-HSPG interactions in embryonic patterning was recently challenged (16). In that report, transgenic mice made deficient in two ShhNp CW amino acid residues implicated in HS binding (17) lacked an Shh-related phenotype, suggesting that direct morphogen-HS interactions were not essential for normal development.…”

mentioning

confidence: 99%

Dual Roles of the Cardin-Weintraub Motif in Multimeric Sonic Hedgehog

Farshi¹,

Ohlig²,

Pickhinke³

et al. 2011

Journal of Biological Chemistry

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The fly morphogen Hedgehog (Hh) and its mammalian orthologs, Sonic, Indian, and Desert hedgehog, are secreted signaling molecules that mediate tissue patterning during embryogenesis and function in tissue homeostasis and regeneration in the adult. The function of all Hh family members is regulated at the levels of morphogen multimerization on the surface of producing cells, multimer release, multimer diffusion to target cells, and signal reception. These mechanisms are all known to depend on interactions of positively charged Hh amino acids (the Cardin-Weintraub (CW) motif) with negatively charged heparan sulfate (HS) glycosaminoglycan chains. However, a precise mechanistic understanding of these interactions is still lacking. The proteins of the Hh family are powerful morphogens that control growth and patterning of developing embryos. Current models for Hh activity suggest that the morphogen disperses from a localized source and forms a gradient that patterns fields of responsive cells expressing the Hh receptor Patched (Ptc).Genetic evidence suggests that this process critically depends on heparan sulfate proteoglycan (HSPG) 2 expression. Upon secretion to the cell surface, Drosophila Hh forms nanoscale oligomers on the cell surface that co-localize with HSPGs (1). HS binds to the Cardin-Weintraub (CW) motif found on all known Hhs and regulates their function in flies (2, 3) and mice (4). In Drosophila (5) as well as in mammalian cell culture (6, 7), Hhs are always released from producing cells in multimeric form, as demonstrated by gel filtration analysis of the soluble morphogen. Release of the multimeric morphogen (the processed Hh N-terminal signaling domain, designated HhNp) from the cell surface depends on the expression of Dispatched (8) and A disintegrin and metalloprotease (ADAM) family members that mediate ectodomain shedding from transfected Bosc23 cells (9). HS is involved in the formation of the HhNp extracellular gradient, which, in the fly, depends on the expression of the Drosophila Exostosin (Ext) family of proteins, encoded by the genes tout velu (ttv), brother of tout velu, and sister of tout velu and the glycosylphosphatidylinositollinked HSPGs Dally and Dally-like, corresponding to vertebrate glypicans (2, 3, 10). HS expression and Dally-like/glypican expression are also essential for signal reception and modulation on Ptc-expressing receiving cells (10 -14) and participate in HhNp-Ihog interaction (15). However, the essential role of direct morphogen-HSPG interactions in embryonic patterning was recently challenged (16). In that report, transgenic mice made deficient in two ShhNp CW amino acid residues implicated in HS binding (17) lacked an Shh-related phenotype, suggesting that direct morphogen-HS interactions were not essential for normal development. However, in that report as well as in others (16 -18), CW-dependent HS interactions were characterized using a recombinant, non-physiological monomeric morphogen termed ShhN, whereas embryogenesis depends entirely on the activity of morp...

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“…Ligand-dependent activation of Hh signaling is associated with tumorigenesis in a subset of epithelial cancers, including colon, pancreatic and ovarian cancer (Theunissen and de Sauvage, 2009), and HSPGs regulate Shh activity and Shh-dependent cancer cell proliferation (Chan et al, 2009). Importantly, Hh does not activate autocrine cancer cell signaling, but instead signals to the stromal compartment (Tian et al, 2009;Yauch et al, 2008), which in turn provides a more favorable environment for tumor growth.…”

Section: The Heparan Sulfate Source Determines Shh Processingmentioning

confidence: 99%

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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Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses

Cited by 72 publications

References 50 publications

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

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

Dual Roles of the Cardin-Weintraub Motif in Multimeric Sonic Hedgehog

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

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