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).

Abstract

Hedgehog (Hh) induces signaling by promoting the reciprocal trafficking of its receptor Patched (Ptc) and the signal transducer Smoothened (Smo), which is inhibited by Ptc, at the cell surface. We identified Smurf family E3 ubiquitin ligases as essential for Smo ubiquitylation and cell surface clearance and demonstrated that Smurf family members mediate the reciprocal trafficking of Ptc and Smo in Drosophila melanogaster. G protein–coupled receptor kinase 2 (Gprk2)–mediated phosphorylation of Smurf promoted Smo ubiquitylation by increasing the recruitment of Smurf to Smo, whereas protein kinase A (PKA)–mediated phosphorylation of Smo caused Smurf to dissociate from Smo, thereby inhibiting Smo ubiquitylation. Smo and Ptc competed for the same pool of Smurf family E3 ubiquitin ligases, and Hh promoted Ptc ubiquitylation and degradation by disrupting the association of Smurf family E3 ubiquitin ligases with Smo and stimulating their binding to Ptc. Our study identifies the E3 ubiquitin ligases that target Smo and provides insight into how Hh regulates the reciprocal trafficking of its receptor and signal transducer.

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