Hh-Np binds GPC5

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). <br><br> 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).

Hh-Np信号梯度的建立部分受到配体与分泌细胞细胞外基质（ECM）中肝素硫酸蛋白聚糖（HSPGs）相互作用的调节。HSPGs的相互作用可以影响Hh寡聚化，并影响Hh配体的横向和长距离扩散（详见Gallet，2011；Briscoe和Therond，2013）。HSPGs的相互作用根据背景和涉及的特定蛋白聚糖，可以刺激或限制Hh信号传导（例如，参见Witt等人，2013；Li等人，2011；Capurro等人，2005；Capurro等人，2012；详见Gallet，2011）。在脊椎动物细胞中，GPI锚定的HSPG糖蛋白5（GPC5）已被证明通过促进SHH配体与PTCH1受体的相互作用来刺激Hh信号传导（Li等人，2011；Witt等人，2013）。SHH和PTCH1的结合依赖于GPC5的GAG链，因为缺乏GAG插入位点的版本在配体和受体结合方面均受损，这些蛋白质不能刺激Hh信号传导（Li等人，2011）。在20%的横纹肌肉瘤中观察到GPC5的扩增（Williamson等人，2007），这些细胞中Hh信号传导的异常激活促进了细胞增殖（Li等人，2011）。