Hh-Np binds GPC5

Stable Identifier
Reaction [binding]
Homo sapiens
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The establishment of a signaling gradient of Hh-Np is modulated in part by the interaction of the ligand with heparin sulphate proteoglycans (HSPGs) in the extracellular matrix (ECM) of the secreting cell. Interactions with HSPGs can influence Hh oligomerization and also impact the lateral and long-range spread of Hh ligand (reviewed in Gallet, 2011; Briscoe and Therond, 2013). Interactions with HSPGs can stimulate or restrict Hh signaling depending on the context and the particular proteoglycans involved (see for instance Witt et al, 2013; Li et al, 2011; Capurro et al, 2005; Capurro et al, 2012; reviewed in Gallet, 2011).

In vertebrate cells, the GPI-anchored HSPG glypican 5 (GPC5) has been shown to stimulate Hh signaling by promoting the interaction between SHH ligand and the PTCH1 receptor (Li et al, 2011; Witt et al, 2013). SHH and PTCH1 binding depends on the GAG chains of GPC5, as versions lacking the GAG insertion sites are compromised for both ligand and receptor binding, and these proteins do not stimulate Hh signaling (Li et al, 2011). Amplification of GPC5 has been observed in 20% of rhabdomyosarcomas (Williamson et al, 2007), and aberrant activation of Hh signaling in these cells promotes cellular proliferation (Li et al, 2011).

Literature References
PubMed ID Title Journal Year
18477453 Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding

Xu, P, Filmus, J, Li, F, Capurro, MI, Jia, A, Shi, W

Dev. Cell 2008
17210683 Role for amplification and expression of glypican-5 in rhabdomyosarcoma

Workman, P, Pritchard-Jones, K, Murai, K, Gordon, T, Selfe, J, Jones, P, Williamson, D, Lu, YJ, Shipley, J

Cancer Res. 2007
21339334 Glypican-5 stimulates rhabdomyosarcoma cell proliferation by activating Hedgehog signaling

Filmus, J, Li, F, Capurro, M, Shi, W

J. Cell Biol. 2011
21257310 Hedgehog morphogen: from secretion to reception

Gallet, A

Trends Cell Biol. 2011
22467855 LRP1 mediates Hedgehog-induced endocytosis of the GPC3-Hedgehog complex

Filmus, J, Capurro, MI, Shi, W

J. Cell. Sci. 2012
23719536 The mechanisms of Hedgehog signalling and its roles in development and disease

Thérond, PP, Briscoe, J

Nat. Rev. Mol. Cell Biol. 2013
23867465 Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-iduronic acid function as Sonic Hedgehog co-receptors to promote proliferation

Segal, RA, Seeberger, PH, Noti, C, Witt, RM, Cohen, SM, Chan, JA, Pazyra-Murphy, MF, Hopwood, JJ, van Kuppevelt, TH, Fuller, M, Hecht, ML

J. Biol. Chem. 2013
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