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Hedgehog ligand biogenesis

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-5358346

PubChem

R-HSA-5358346

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).

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying entries **1 - 10** of 30 in total

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
O00231	26S proteasome non-ATPase regulatory subunit 11	PSMD11	view
O00487	Ubiquitin C-terminal hydrolase PSMD14	POH1 PSMD14	view
O14818	Proteasome subunit alpha type-7	HSPC PSMA7	view
O43242	26S proteasome non-ATPase regulatory subunit 3	PSMD3	view
P07237	Protein disulfide-isomerase	ERBA2L P4HB PDI PDIA1 PO4DB	view
P17980	26S proteasome regulatory subunit 6A	PSMC3 TBP1	view
P20618	Proteasome subunit beta type-1	PSC5 PSMB1	view
P25786	Proteasome subunit alpha type-1	HC2 NU PROS30 PSC2 PSMA1	view
P25788	Proteasome subunit alpha type-3	HC8 PSC8 PSMA3	view
P25789	Proteasome subunit alpha type-4	HC9 PSC9 PSMA4	view

Displaying **all 3** entries
GlyCosmos Lectin	UniProt ID	Lectin Name	Pathway Viewer
GL_000990	Q13438	Protein OS-9	view
GL_005369	Q86TM6	E3 ubiquitin-protein ligase synoviolin	view
GL_005506	Q9UBV2	Protein sel-1 homolog 1	view

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