Dual degradation signals destruct GLI1: AMPK inhibits GLI1 through β-TrCP-mediated proteasome degradation
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Rui Zhang1,*, Sherri Y. Huang1,*, Kay Ka-Wai Li2, Yen-Hsing Li1, Wei-Hsuan Hsu1, Guang Jun Zhang3,4, Chun-Ju Chang1,3 and Jer-Yen Yang1,3
1Department of Basic Medical Sciences, West Lafayette, Indiana, USA
25/F of Cancer Centre, Prince of Wales Hospital, Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong
3Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
4Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA
*These authors contributed equally to this work
Jer-Yen Yang, email: email@example.com
Keywords: AMPK, β-transducin repeat containing protein (β-TrCP), Hedgehog, GLI1, medulloblastoma
Received: December 15, 2016 Accepted: April 05, 2017 Published: May 10, 2017
Overexpression of the GLI1 gene has frequently been found in various cancer types, particularly in brain tumors, in which aberrant GLI1 induction promotes cancer cell growth. Therefore, identifying the molecular players controlling GLI1 expression is of clinical importance. Previously, we reported that AMPK directly phosphorylated and destabilized GLI1, resulting in the suppression of the Hedgehog signaling pathway. The current study not only demonstrates that AMPK inhibits GLI1 nuclear localization, but further reveals that β-TrCP plays an essential role in AMPK-induced GLI1 degradation. We found that activation of AMPK promotes the interaction between β-TrCP and GLI1, and induces β-TrCP-mediated GLI1-ubiquitination and degradation. Inhibiting AMPK activity results in the dissociation of the β-TrCP and GLI1 interaction, and diminishes β-TrCP-mediated-GLI1 ubiquitination and degradation. On GLI1, substitution of AMPK phosphorylation sites to aspartic acid (GLI13E) results in stronger binding affinity of GLI1 with β-TrCP, accompanied by enhanced GLI1 ubiquitination and later degradation. In contrast, the GLI1 alanine mutant (GLI13A) shows weaker binding with β-TrCP, which is accompanied by reduced β-TrCP-mediated ubiquitination and degradation. Together, these results demonstrate that AMPK regulates GLI1 interaction with β-TrCP by phosphorylating GLI1 and thus both post-translational modifications by AMPK and β-TrCP ultimately impact GLI1 degradation.
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