2. Academic Validation
  3. Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis

Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis

  • Cell Rep. 2022 Dec 20;41(12):111834. doi: 10.1016/j.celrep.2022.111834.
Huan Li 1,  Jie Zhang 2,  Jing-Ru Ke 3,  Ze Yu 2,  Run Shi 2,  Shan-Shan Gao 2,  Jing-Feng Li 2,  Zhen-Xing Gao 2,  Chang-Shu Ke 4,  Hui-Xia Han 5,  Jiang Xu 6,  Qibin Leng 2,  Gui-Ru Wu 2,  Yingqiu Li 7,  Lin Tao 8,  Xianghui Zhang 9,  Man-Sun Sy 10,  Chaoyang Li 11
Affiliations

Affiliations

  • 1 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong High Education Institute, 78 Heng Zhi Gang Road, Guangzhou 510095, China; Wuhan Institute of Virology, Chinese Academy of Sciences, 44 Xiao Hong Shan Zhong Qu, Wuhan 430030, China.
  • 2 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong High Education Institute, 78 Heng Zhi Gang Road, Guangzhou 510095, China.
  • 3 Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China.
  • 4 Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China.
  • 5 Department of Pathology, School of Basic Medical Sciences, Southern Medical University, No. 1023-1063 Shatai South Road, Guangzhou 510515, China.
  • 6 Department of Stomatology, First Affiliated Hospital, School of Medicine, Shihezi University, No. 107 North 2nd Road, Shihezi 832008, China.
  • 7 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, 135 West Xingang Road, Guangzhou 510275, China.
  • 8 Department of Pathology, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832008, China.
  • 9 Department of Public Health, Shihezi University School of Medicine, Shihezi 832000, China.
  • 10 Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
  • 11 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong High Education Institute, 78 Heng Zhi Gang Road, Guangzhou 510095, China. Electronic address: chaoyangli@gzhmu.edu.cn.
PMID: 36543142 DOI: 10.1016/j.celrep.2022.111834
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.

Keywords

CP: Cell biology; CP: Molecular biology; adaptor protein; autophagy; melanoma; metastasis; prion protein; receptor tyrosine kinase; treatment; ubiquitination.

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