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Patched-1 pro-apoptotic activity is downregulated by modification of K1413 by the E3 ubiquitin-protein ligase Itchy homolog

Xiaole L. Chen, Pilar Chinchilla, Joanna Fombonne, Lan Ho, Catherine Guix, James H. Keen, Patrick Mehlen, Natalia A. Riobo
Xiaole L. Chen
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USAa
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Pilar Chinchilla
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USAa
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Joanna Fombonne
Apoptosis, Cancer and Development Laboratory - Equipe labellisée ‘La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon, Franceb
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Lan Ho
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USAa
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Catherine Guix
Apoptosis, Cancer and Development Laboratory - Equipe labellisée ‘La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon, Franceb
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James H. Keen
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USAa
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USAc
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Patrick Mehlen
Apoptosis, Cancer and Development Laboratory - Equipe labellisée ‘La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon, Franceb
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Natalia A. Riobo
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USAa
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USAc
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  • For correspondence: natalia.riobo@jefferson.edu
DOI: 10.1128/MCB.00960-14
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ABSTRACT

The Hedgehog (Hh) receptor Patched1 (PTCH1) opposes the activation of Gli transcription factors and induces cell death through a Gli-independent pathway. Here, we report that the C-terminal domain (CTD) of PTCH1 interacts with and is ubiquitylated on K1413 by E3 ubiquitin-protein ligase Itchy homolog (Itch), a Nedd4 family member. Itch induces ubiquitylation of K1413, reduction of PTCH1 at the plasma membrane and degradation, activating Gli transcriptional activity in the absence of Hh ligands. Silencing of Itch stabilizes PTCH1 and increases its plasma membrane retention. Itch is the preferential PTCH1 E3 ligase in the absence of Hh ligands, since of the other seven Nedd4 family members only WW domain-containing protein 2 (WWP2) showed a minor redundant role. Like Itch depletion, mutation of the ubiquitylation site (K1314R) resulted in accumulation of PTCH1 at the plasma membrane, prolongation of its half-life, and increase cell death by hyperactivation of caspase-9. Remarkably, Itch is the main determinant of PTCH1 stability under resting conditions but not in response in the presence of Sonic Hedgehog. In conclusion, our findings reveal that Itch is a key regulator of ligand-independent Gli activation and noncanonical Hh signaling by the governance of basal PTCH1 internalization and degradation.

FOOTNOTES

  • ↵#Address correspondence to Natalia A. Riobo, natalia.riobo{at}jefferson.edu
  • Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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Patched-1 pro-apoptotic activity is downregulated by modification of K1413 by the E3 ubiquitin-protein ligase Itchy homolog
Xiaole L. Chen, Pilar Chinchilla, Joanna Fombonne, Lan Ho, Catherine Guix, James H. Keen, Patrick Mehlen, Natalia A. Riobo
Molecular and Cellular Biology Aug 2014, MCB.00960-14; DOI: 10.1128/MCB.00960-14

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Patched-1 pro-apoptotic activity is downregulated by modification of K1413 by the E3 ubiquitin-protein ligase Itchy homolog
Xiaole L. Chen, Pilar Chinchilla, Joanna Fombonne, Lan Ho, Catherine Guix, James H. Keen, Patrick Mehlen, Natalia A. Riobo
Molecular and Cellular Biology Aug 2014, MCB.00960-14; DOI: 10.1128/MCB.00960-14
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