The Patched dependence receptor triggers apoptosis through a DRAL–caspase-9 complex

Abstract

Sonic hedgehog (Shh) and its main receptor Patched (Ptc) are implicated in both neural development and tumorigenesis1, 2. Beside the classic morphogen activity of Shh, Shh is also a survival factor3, 4. Along this line, Ptc has been shown to function as a dependence receptor, inducing apoptosis in the absence of Shh, while its pro-apoptotic activity is blocked in Shh presence5. Here we show that, in the absence of its ligand, Ptc interacts with the adaptor protein DRAL/FHL2. DRAL/FHL2 is required for the pro-apoptotic activity of Ptc both in immortalized cells and during neural tube development in chick embryo. We demonstrate that, in the absence of Shh, Ptc recruits a protein complex that includes DRAL, the CARD containing domain proteins TUCAN or NALP1 and the apical caspase-9. Ptc triggers caspase-9 activation and enhances cell death via a caspase-9-dependent mechanism. Thus, we propose that, upon absence of its ligand Shh, the dependence receptor Ptc serves as the anchor for a caspase-activating complex that includes DRAL, a CARD domain containing protein and caspase-9.

Guidance Molecules in Axon Pruning and Cell Death

“…The SHH receptor Patched was later shown to have an intrinsic pro-apoptotic activity both in vitro and in the chick neural tube, which could be rescued by SHH stimulation, consistent with a dependence receptor activity (Thibert et al 2003). More recently, the signaling pathway underlying Patched-mediated apoptosis was shown to involve direct interaction with a proapoptotic complex comprising caspase 9 and the adaptor protein DRAL (Mille et al 2009). As SHH and Netrins both have attractant effects on commissural neurons, it will be interesting to test how each cue interacts with the other to coordinate, not only the navigation, but also the survival of similar neuronal populations.…”

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…Ptc was indeed found to interact through its ADD, and only in the absence of its ligand Shh, with DRAL/FHL2 (Mille et al, 2009b). DRAL was already known to promote apoptosis through an unknown mechanism in a wide variety of cells when overexpressed (Scholl et al, 2000) and to interact with TUCAN, a CARD-containing adaptor protein for caspases 1 and 9 (Stilo et al, 2002).…”

“…Interestingly, it was demonstrated that Shh functions as a survival factor by inhibiting the apoptotic function of Ptc and that this proapoptotic function is crucial for adequate neural tube development (Thibert et al, 2003;Mille et al, 2009b).…”

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

“…Thus, in the absence of their ligands, some dependence receptors like Patched and DCC appear to interact with the cytoplasmic adaptor protein DRAL to assemble a caspase-9-activating platform. 55 Another dependence receptor, UNC5B, responds to the withdrawal of netrin-1 by recruiting a signaling complex that includes protein phosphatase 2A (PP2A) and death-associated protein kinase 1 (DAPK1). 56 This multiprotein interaction would lead to the PP2A-mediated dephosphorylation of DAPK, in turn unleashing its multifaceted pro-apoptotic potential.…”