Research ArticleCell Biology

Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases

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Sci. Signal.  06 Feb 2018:
Vol. 11, Issue 516, eaan8660
DOI: 10.1126/scisignal.aan8660

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Smurf controls reciprocal trafficking of Smo and Ptc

Hedgehog (Hh) stimulates intracellular signaling by binding to Patched (Ptc) at the cell surface, relieving Ptc-mediated repression of the transmembrane protein Smoothened (Smo). Hh also stimulates the ubiquitylation and internalization of Ptc. In the absence of Hh, Smo is inactivated and targeted for ubiquitylation and removal from the membrane. Li et al. identified Smurf family ubiquitin E3 ligases as required for this reciprocal regulation of Ptc and Smo in Drosophila melanogaster. The ability of Smurf to bind to and ubiquitylate Smo depended on phosphorylation of Smurf by G protein–coupled receptor kinase 2 (Gprk2) and was inhibited by Hh-induced phosphorylation of Smo. Hh-induced dissociation of Smurf from Smo freed Smurf to interact with Ptc, thus promoting the ubiquitylation of Ptc. These findings identify Smurf family E3 ligases as key players in the reciprocal accumulation of Smo and Ptc at the cell surface (see Focus by Sharpe and de Sauvage).