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).