TY - JOUR
T1 - Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases
AU - Li, Shuang
AU - Li, Shuangxi
AU - Wang, Bing
AU - Jiang, Jin
N1 - Funding Information:
This work was supported by grants from the NIH (GM118063) and Welch Foundation (I-1603) to J.J. J.J. is a Eugene McDermott Endowed Scholar in Biomedical Science at the University of Texas Southwestern Medical Center. Author contributions: J.J. and Shuang Li designed the experiments; Shuang Li, Shuangxi Li, and B.W. performed the experiments; Shuang Li, Shuangxi Li, and J.J. analyzed the data; and J.J. wrote the manuscript. Competing interests: The authors declare that they have no competing interests.
PY - 2018/2/6
Y1 - 2018/2/6
N2 - 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.
AB - 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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U2 - 10.1126/scisignal.aan8660
DO - 10.1126/scisignal.aan8660
M3 - Article
C2 - 29438012
AN - SCOPUS:85041495714
VL - 11
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1937-9145
IS - 516
ER -