Hh-Np binds to DISP2

Stable Identifier
Reaction [binding]
Homo sapiens
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Long range signaling of Hh depends on a number of additional factors that promote the release and spread of Hh-Np ligand. Dispatched2 (DISP2) is a 12-pass transmembrane protein that was identified as being required for release and long-range signaling by Hh-Np (Burke et al, 1999; Ma et al, 2002; Nakano et al, 2004). In mammals, DISP2 has been shown to bind directly to the cholesterol moiety of Hh-Np through its first extracellular region, and this interaction is required for secretion and long-range signaling. Mutants of DISP2 that are inactive in promoting Hh long-range signaling show tighter binding to Hh-Np, suggesting that these mutants interfere with the release of Hh ligand from the plasma membrane (Tukachinsky et al, 2012). Although this pathway shows DISP2 and Hh-Np interacting at the plasma membrane, it is possible that the interaction occurs earlier in the secretory pathway and that DISP2 escorts Hh-Np to the cell surface.

In addition to binding to DISP2, the cholesterol moiety of Hh-Np is also bound by the secreted protein SCUBE2 (Tukachinsky et al, 2012; Creanga et al, 2012). Like DISP2, SCUBE2 is required for long-range signaling by Hh-Np (Johnson et al, 2012; Tukachinsky et al, 2012; Creanga et al, 2012). DISP2 and SCUBE2 recognize distinct portions of the cholesterol group on Hh-Np, suggesting a possible hand-off mechanism at the plasma membrane that allows the release of Hh from the secreting cell (Tukachinsky et al, 2012; Creanga et al, 2012).
Literature References
PubMed ID Title Journal Year
22609552 Scube activity is necessary for Hedgehog signal transduction in vivo

Ayers, K, Hall, TE, Mitchell, C, Dyson, JM, Johnson, JL, Currie, PD, Hollway, GE, Berger, S, Sonntag, C, Gautier, P

Dev. Biol. 2012
10619433 Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells

Hafen, E, Senti, KA, Bellotto, M, Nellen, D, Burke, R, Basler, K, Dickson, BJ

Cell 1999
22902404 Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand

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

Cell Rep 2012
15110707 Inactivation of dispatched 1 by the chameleon mutation disrupts Hedgehog signalling in the zebrafish embryo

Kim, HR, Schier, AF, Kawakami, A, Nakano, Y, Roy, S, Ingham, PW

Dev. Biol. 2004
12372301 Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched

Beachy, PA, Erkner, A, Gong, R, Taipale, J, Ma, Y, Basler, K, Yao, S

Cell 2002
22677548 Scube/You activity mediates release of dually lipid-modified Hedgehog signal in soluble form

Beachy, PA, Talbot, WS, Saunders, AM, Mann, RK, Glenn, TD, Creanga, A

Genes Dev. 2012
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