Hedgehog ligand biogenesis (Homo sapiens)
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Description
Mammalian genomes encode three Hedgehog ligands, Sonic Hedgehog (SHH), Indian Hedgehog (IHH) and Desert Hedgehog (DHH). These secreted morphogens can remain associated with lipid rafts on the surface of the secreting cell and affect developmental processes in adjacent cells. Alternatively, they can be released by proteolysis or packaging into vesicles or lipoprotein particles and dispersed to act on distant cells. SHH activity is required for organization of the limb bud, notochord and neural plate, IHH regulates bone and cartilage development and is partially redundant with SHH, and DHH contributes to germ cell development in the testis and formation of the peripheral nerve sheath (reviewed in Pan et al, 2013).
Despite divergent biological roles, all Hh ligands are subject to proteolytic processing and lipid modification during transit to the surface of the secreting cell (reviewed in Gallet, 2011). Precursor Hh undergoes autoproteolytic cleavage mediated by the C-terminal region to yield an amino-terminal peptide Hh-Np (also referred to as Hh-N) (Chen et al, 2011). No other well defined role for the C-terminal region of Hh has been identified, and the secreted Hh-Np is responsible for all Hh signaling activity. Hh-Np is modified with cholesterol and palmitic acid during transit through the secretory system, and both modifications contribute to the activity of the ligand (Porter et al, 1996; Pepinsky et al, 1998; Chamoun et al, 2001).
At the cell surface, Hh-Np remains associated with the secreting cell membrane by virtue of its lipid modifications, which promote clustering of Hh-Np into lipid rafts (Callejo et al, 2006; Peters et al, 2004). Long range dispersal of Hh-Np depends on the untethering of the ligand from the membrane through a variety of mechanisms. These include release of monomers through the combined activity of the transmembrane protein Dispatched (DISP2) and the secreted protein SCUBE2, assembly into soluble multimers or apolipoprotein particles or release on the surface of exovesicles (Vyas et al, 2008; Tukachinsky et al, 2012; Chen 2004; Zeng et al, 2001; reviewed in Briscoe and Therond, 2013). View original pathway at:Reactome.
Despite divergent biological roles, all Hh ligands are subject to proteolytic processing and lipid modification during transit to the surface of the secreting cell (reviewed in Gallet, 2011). Precursor Hh undergoes autoproteolytic cleavage mediated by the C-terminal region to yield an amino-terminal peptide Hh-Np (also referred to as Hh-N) (Chen et al, 2011). No other well defined role for the C-terminal region of Hh has been identified, and the secreted Hh-Np is responsible for all Hh signaling activity. Hh-Np is modified with cholesterol and palmitic acid during transit through the secretory system, and both modifications contribute to the activity of the ligand (Porter et al, 1996; Pepinsky et al, 1998; Chamoun et al, 2001).
At the cell surface, Hh-Np remains associated with the secreting cell membrane by virtue of its lipid modifications, which promote clustering of Hh-Np into lipid rafts (Callejo et al, 2006; Peters et al, 2004). Long range dispersal of Hh-Np depends on the untethering of the ligand from the membrane through a variety of mechanisms. These include release of monomers through the combined activity of the transmembrane protein Dispatched (DISP2) and the secreted protein SCUBE2, assembly into soluble multimers or apolipoprotein particles or release on the surface of exovesicles (Vyas et al, 2008; Tukachinsky et al, 2012; Chen 2004; Zeng et al, 2001; reviewed in Briscoe and Therond, 2013). View original pathway at:Reactome.
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Hh
fragments:ERLEC/OS9:SEL1:SYVN1dimer:DERL2:VCP hexamerHh
fragments:OS9/ERLEC1dimer:DERL2:VCP
hexamerprocessing
variants:ERLEC:OS9:SEL1:SYVN1 dimer:DERL2:VCP hexamerHh
fragments:ERLEC/OS9:SEL1:SYVN1dimer:DERL2:VCP hexamerprocessing
variants:ERLEC:OS9:SEL1:SYVN1 dimer:DERL2:VCP hexamerAnnotated Interactions
Hh
fragments:ERLEC/OS9:SEL1:SYVN1dimer:DERL2:VCP hexamerHh
fragments:ERLEC/OS9:SEL1:SYVN1dimer:DERL2:VCP hexamerHh
fragments:ERLEC/OS9:SEL1:SYVN1dimer:DERL2:VCP hexamerHh
fragments:OS9/ERLEC1Hh
fragments:OS9/ERLEC1Prior to the autoproteolytic cleavage reaction, the protein disulphide isomerase P4HB is required to reduce the intramolecular disulphide, freeing the catalytic cysteine side chain for nucleophilic attack. Mutational analysis and co-immunoprecipitation studies support a model where the N-terminal CXXC motif of P4HB forms a mixed disulphide with the non-catalytic cysteine residue of the Hh precursor (Chen et al, 2011.
In addition to binding to DISP2, the cholesterol moiety of Hh-Np is also bound by the secreted protein SCUBE2 (Tukachinsky et al, 2012; Creanga et al, 2012). Like DISP2, SCUBE2 is required for long-range signaling by Hh-Np (Johnson et al, 2012; Tukachinsky et al, 2012; Creanga et al, 2012). DISP2 and SCUBE2 recognize distinct portions of the cholesterol group on Hh-Np, suggesting a possible hand-off mechanism at the plasma membrane that allows the release of Hh from the secreting cell (Tukachinsky et al, 2012; Creanga et al, 2012).
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).
dimer:DERL2:VCP
hexamerdimer:DERL2:VCP
hexamerdimer:DERL2:VCP
hexamerdimer:DERL2:VCP
hexamerprocessing
variants:ERLEC:OS9:SEL1:SYVN1 dimer:DERL2:VCP hexamerprocessing
variants:ERLEC:OS9:SEL1:SYVN1 dimer:DERL2:VCP hexamerprocessing
variants:ERLEC:OS9:SEL1:SYVN1 dimer:DERL2:VCP hexamerHh
fragments:ERLEC/OS9:SEL1:SYVN1dimer:DERL2:VCP hexamerHh
fragments:ERLEC/OS9:SEL1:SYVN1dimer:DERL2:VCP hexamerHh
fragments:ERLEC/OS9:SEL1:SYVN1dimer:DERL2:VCP hexamerprocessing
variants:ERLEC:OS9:SEL1:SYVN1 dimer:DERL2:VCP hexamerprocessing
variants:ERLEC:OS9:SEL1:SYVN1 dimer:DERL2:VCP hexamerprocessing
variants:ERLEC:OS9:SEL1:SYVN1 dimer:DERL2:VCP hexamer