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Review
. 2008 Apr;294(4):G844-9.
doi: 10.1152/ajpgi.00564.2007. Epub 2008 Jan 31.

The adventures of sonic hedgehog in development and repair. III. Hedgehog processing and biological activity

Shohreh F Farzan  1 , Samer Singh, Neal S Schilling, David J Robbins
Affiliations
Review

The adventures of sonic hedgehog in development and repair. III. Hedgehog processing and biological activity

Shohreh F Farzan et al. Am J Physiol Gastrointest Liver Physiol. 2008 Apr.

Abstract

The Hedgehog (Hh) family of secreted proteins is necessary for aspects of the development and maintenance of the gastrointestinal tract. Hh is thought to function as a morphogen, a mitogen, a cell survival factor, and an axon guidance factor. Given its wide role in development, as well as in a variety of disease states, understanding the regulation of Hh function and activity is critically important. However, the study of Hh signaling has been impeded by its unusual biology. Hh is unique in that it is the only protein covalently modified by cholesterol, which in turn affects numerous aspects of its localization, release, movement, and activity. All are important factors when considering Hh's physiological role, and animals have developed an intricate system of regulators responsible for both promoting and inhibiting the activity of Hh. This review is intended to give a broad overview of how the biosynthesis and movement of Hh contributes to its biological activity.

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Figures

Figure 1
Figure 1. Hh activity
Hh can exist in multiple forms, each with varying levels of activity and physiological relevance. Hh that is dually modified has been shown to have more activity than unmodified Hh, but overall palmitoylation appears to have the most effect on activity. Unmodified Hh and Hh that has been singly modified by palmitate have not been found to exist in vivo.
Figure 2
Figure 2. Overview of Hh production and movement
The Hh producing cell shown in the left panel outlines the various steps in Hh modification before its release by Disp. Hh is produced as a pre-protein, represented in three domains; a signal sequence (S-yellow), an amino-terminal domain (N-blue), and a carboxy-terminal domain (C-red). The signal sequence is cleaved to produce a full-length unmodified form of Hh. An autocatalyic reaction removes the carboxy-terminus and attaches a cholesterol moiety (C-green) to the newly formed carboxy-terminus. Hh is then further modified by the addition of a palmitate (P-orange), a reaction catalyzed by Ski. The dually modified form of Hh is then released by Disp to the cell surface as a monomer or to the extracellular compartment in a multimeric form. The right panel represents a Hh receiving cell. The movement of Hh is aided or inhibited by various factors. Proteins such as HSPGs, megalin and the family of Ihog proteins serve as positive regulators (green), either by promoting its movement, enhancing the Hh signal or assisting its binding to Ptc. Negative regulators (red), such as Hip and Ptc, prevent Hh movement or serve to bind up excess Hh. Freely diffusible factors have been identified in some animals and are represented as binding to Hh in the extracellular matrix. Ultimately, Hh must bind to its receptor, Ptc, in order to activate the transcription of varius target genes.
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