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Release of Hh-Np from the secreting cell
Stable Identifier
R-HSA-5362798
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
Locations in the PathwayBrowser
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Signal Transduction (Homo sapiens)
Signaling by Hedgehog (Homo sapiens)
Hedgehog ligand biogenesis (Homo sapiens)
Release of Hh-Np from the secreting cell (Homo sapiens)
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Cholesterol and palmitoyl-modification of Hh-Np render the ligand highly hydrophobic and results in its close association with the plasma membrane of the producing cell after secretion. Hh-Np tethered in this way may cluster in sterol-rich lipid rafts where it is competent for short-range signaling. Cell surface Hh-Np also interacts with glypican components of the extracellular matrix and this interaction stabilizes the ligand and is required for its lateral spread. Together, clustering into lipid rafts and interaction with HSPGs may favour packaging of ligand into higher order forms required for ligand dispersal.
Long-range signaling requires release of Hh-Np from the secreting cell. Release is achieved through a number of possibly overlapping mechanisms. These include oligomerization into micelle-like structures, packaging into lipoprotein particles and interaction with cholesterol-binding adaptor proteins such as DISP and SCUBE2. In addition, Hh-Np can be released from the plasma membrane through proteolytic cleavage: NOTUM is a secreted enzyme that is thought to promote the release of Hh-Np by cleaving the GPI anchor of Hh-associated glypicans, while the transmembrane metalloprotease ADAM17 promotes long-range Hh signaling by removing the palmitoyl- and cholesterol-modified N- and C-termini of the membrane-associated ligand. How all these mechanisms are coordinated remains to be elucidated (reviewed in Briscoe and Therond, 2013; Gallet, 2011).
Literature References
PubMed ID
Title
Journal
Year
21257310
Hedgehog morphogen: from secretion to reception
Gallet, A
Trends Cell Biol.
2011
23719536
The mechanisms of Hedgehog signalling and its roles in development and disease
Thérond, PP
,
Briscoe, J
Nat. Rev. Mol. Cell Biol.
2013
Participants
Events
Hh-Np binds to DISP2
(Homo sapiens)
Hh-Np binds SCUBE2 in the extracellular region to promote long-range signalling
(Homo sapiens)
Hh-Np binds GPC5
(Homo sapiens)
NOTUM releases Hh-Np:GPC5 from the plasma membrane
(Homo sapiens)
Hh-Np is cleaved by ADAM17 to promote ligand shedding
(Homo sapiens)
Participates
as an event of
Hedgehog ligand biogenesis (Homo sapiens)
Orthologous Events
Release of Hh-Np from the secreting cell (Bos taurus)
Release of Hh-Np from the secreting cell (Canis familiaris)
Release of Hh-Np from the secreting cell (Danio rerio)
Release of Hh-Np from the secreting cell (Drosophila melanogaster)
Release of Hh-Np from the secreting cell (Gallus gallus)
Release of Hh-Np from the secreting cell (Mus musculus)
Release of Hh-Np from the secreting cell (Rattus norvegicus)
Release of Hh-Np from the secreting cell (Sus scrofa)
Release of Hh-Np from the secreting cell (Xenopus tropicalis)
Authored
Rothfels, K (2014-04-16)
Reviewed
Liu, Y C (2014-05-16)
Created
Rothfels, K (2014-04-17)
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