Hedgehog ligand biogenesis

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R-HSA-5358346
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Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
8824192 Cholesterol modification of hedgehog signaling proteins in animal development

Porter, JA, Young, KE, Beachy, PA

Science 1996
16396909 Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix

Callejo, A, Torroja, C, Quijada, L, Guerrero, I

Development 2006
18585355 Nanoscale organization of hedgehog is essential for long-range signaling

Vyas, N, Goswami, D, Manonmani, A, Sharma, P, Ranganath, HA, VijayRaghavan, K, Shashidhara, LS, Sowdhamini, R, Mayor, S

Cell 2008
21257310 Hedgehog morphogen: from secretion to reception

Gallet, A

Trends Cell Biol. 2011
22902404 Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand

Tukachinsky, H, Kuzmickas, RP, Jao, CY, Liu, J, Salic, A

Cell Rep 2012
11395778 A freely diffusible form of Sonic hedgehog mediates long-range signalling

Zeng, X, Goetz, JA, Suber, LM, Scott WJ, Jr, Schreiner, CM, Robbins, DJ

Nature 2001
15163793 The cholesterol membrane anchor of the Hedgehog protein confers stable membrane association to lipid-modified proteins

Peters, C, Wolf, A, Wagner, M, Kuhlmann, J, Waldmann, H

Proc. Natl. Acad. Sci. U.S.A. 2004
23719536 The mechanisms of Hedgehog signalling and its roles in development and disease

Briscoe, J, Thérond, PP

Nat. Rev. Mol. Cell Biol. 2013
11486055 Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal

Chamoun, Z, Mann, RK, Nellen, D, von Kessler, DP, Bellotto, M, Beachy, PA, Basler, K

Science 2001
23565096 A review of hedgehog signaling in cranial bone development

Pan, A, Chang, L, Nguyen, A, James, AW

Front Physiol 2013
15075292 Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates

Chen, MH, Li, YJ, Kawakami, T, Xu, SM, Chuang, PT

Genes Dev. 2004
21357747 Processing and turnover of the Hedgehog protein in the endoplasmic reticulum

Chen, X, Tukachinsky, H, Huang, CH, Jao, C, Chu, YR, Tang, HY, Mueller, B, Schulman, S, Rapoport, TA, Salic, A

J. Cell Biol. 2011
9593755 Identification of a palmitic acid-modified form of human Sonic hedgehog

Pepinsky, RB, Zeng, C, Wen, D, Rayhorn, P, Baker, DP, Williams, KP, Bixler, SA, Ambrose, CM, Garber, EA, Miatkowski, K, Taylor, FR, Wang, EA, Galdes, A

J. Biol. Chem. 1998
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