Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis.
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| Abstract |
Aberrant activation of receptor tyrosine kinase (RTK) is usually a result of mutation and plays important roles in tumorigenesis. How RTK without mutation affects tumorigenesis remains incompletely understood. Here we show that in human melanomas pro-prion (pro-PrP) is an adaptor protein for an E3 ligase c-Cbl, enabling it to polyubiquitinate activated insulin-like growth factor-1 receptor (IGF-1R), leading to enhanced melanoma metastasis. All human melanoma cell lines studied here express pro-PrP, retaining its glycosylphosphatidylinositol-peptide signal sequence (GPI-PSS). The sequence, PVILLISFLI in the GPI-PSS of pro-PrP, binds c-Cbl, docking c-Cbl to the inner cell membrane, forming a pro-PrP/c-Cbl/IGF-1R trimeric complex. Subsequently, IGF-1R polyubiquitination and degradation are augmented, which increases autophagy and tumor metastasis. Importantly, the synthetic peptide PVILLISFLI disrupts the pro-PrP/c-Cbl/IGF-1R complex, reducing cancer cell autophagy and mitigating tumor aggressiveness in vitro and in vivo. Targeting cancer-associated GPI-PSS may provide a therapeutic approach for treating human cancers expressing pro-PrP.
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| Authors | Huan Li, Jie Zhang, Jing-Ru Ke, Ze Yu, Run Shi, Shan-Shan Gao, Jing-Feng Li, Zhen-Xing Gao, Chang-Shu Ke, Hui-Xia Han, Jiang Xu, Qibin Leng, Gui-Ru Wu, Yingqiu Li, Lin Tao, Xianghui Zhang, Man-Sun Sy, Chaoyang Li |
| Journal | Cell reports (Cell Rep) Vol. 41 Issue 12 Pg. 111834 (12 20 2022) ISSN: 2211-1247 [Electronic] United States |
| PMID | 36543142 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. |
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