Dispatched, a Novel Sterol-Sensing Domain Protein Dedicated to the Release of Cholesterol-Modified Hedgehog from Signaling Cells

Abstract

Members of the Hedgehog (Hh) family of secreted signaling proteins function as potent short-range organizers in animal development. Their range of action is limited by a C-terminal cholesterol tether and the upregulation of Patched (Ptc) receptor levels. Here we identify a novel segment-polarity gene in Drosophila, dispatched (disp), and demonstrate that its product is required in sending cells for normal Hh function. In the absence of Disp, cholesterol-modified but not cholesterol-free Hh is retained in these cells, indicating that Disp functions to release cholesterol-anchored Hh. Despite their opposite roles, Disp and Ptc share structural homology in the form of a sterol-sensing domain, suggesting that release and sequestration of cholesterol-modified Hh may be based on related molecular pathways.

Anteroposterior patterning in the limb and digit specification: Contribution of mouse genetics

“…Lewis et al (2001) constructed a mutant mouse strain that constitutively produces a truncated Shh protein (NShh), which cannot undergo cholesterol modification. Rather counterintuitively, and in contrast to the situation in Drosophila (Burke et al, 1999), this finding drastically restricts the Shh target field, as judged by immunohistochemistry of Shh and analysis of expression of Shh target genes. Whereas cholesterol-bound Shh signals over a distance of approximately 300 m (30 cell diameters), the N-Shh acts only over one third of this distance, although it retains similar biological activity.…”

Targeting the CB2 cannabinoid receptor in osteoporosis

“…Shh is synthesized as a propolypeptide that is processed by a unique autocatalytic reaction in which the C-terminal domain catalyzes a cholesterol-dependent internal cleavage of the pro-form that simultaneously attaches a cholesterol moiety to the cleaved N-terminal domain [24]. The autocatalysis is not sufficient for secretion of the mature ligand; this requires the action of an independent membrane protein referred to as Dispatched [25]. Cholesterol-modified mature Shh is inherently highly hydrophobic and this can limit its diffusion away from the cells that secrete it.…”

Tri sélectif et recyclage

“…En d'autres termes, Wntless est peut-être le membre fondateur d'une nouvelle famille de protéines spécifiquement requises pour la sécrétion de glycoprotéines telles que WNT, Hh ou TGFβ (transforming growth factor β). En particulier, on peut se demander si la protéine transmembranaire Dispatched qui est requise pour la sécrétion de Hh [22] est un récepteur de tri comme Wntless. La situation est clairement différente pour le retromer.…”