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Shedding of GPP130 by PC7 and Furin: Potential Implication in Lung Cancer Progression
Priyanka Prabhala1, Stephanie Duval1, Alexandra Evagelidis1
1Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, Montreal, QC H2W 1R7, Canada.
Abstract:
From a previously performed proteomics screen, GPP130, or Golgi phosphoprotein of 130 kDa, was identified as a potential substrate of the proprotein convertase 7 (PC7; PCSK7). GPP130 is a type-II transmembrane protein with a luminal domain containing endosomal and Golgi-retrieval determinants, enabling a unique trafficking route. Most of the previous work on GPP130 relates to its binding and retrograde trafficking of the Shiga toxin. However, its cellular biology and its biochemical characterization remain understudied. Recently, GPP130 was reported to be implicated in cell cycle progression and cell proliferation in head and neck cancer cells. This led us to analyze the cBioPortal for Cancer Genomics, revealing that the GPP130/GOLIM4 gene is amplified in many cancers, including lung, ovarian, and cervical. This observation led us to use the A549 lung cancer cell line to investigate the growth-regulating roles of endogenous and overexpressed GPP130 and to analyze the impact of its cleavage/shedding by PC7 and/or Furin on cellular growth. Our cell-based assays suggest that GPP130 is a novel pro-protein convertase substrate that increases cell proliferation in A549, SKOV3, and HeLa cells, and that the latter activity is enhanced following its cleavage by PC7 and/or Furin into a membrane-bound N-terminal product and secreted C-terminal fragments. This novel work sheds light on the cell biology of the poorly characterized GPP130, its proliferative activity, and modulation upon its shedding by PC7 and Furin in lung cancer progression.
Insights
Golgi phosphoprotein 130 (GPP130) is a novel substrate for proprotein convertase 7 (PC7) and Furin, enhancing cancer cell proliferation. Its cleavage by PC7/Furin increases GPP130
Area of Science:
- Molecular and Cellular Biology
- Cancer Research
- Proteomics
Background:
- Golgi phosphoprotein 130 (GPP130) is a type-II transmembrane protein involved in protein trafficking.
- GPP130's role in cancer cell proliferation and its regulation by proprotein convertases are understudied.
- The GPP130/GOLIM4 gene is amplified in various cancers, including lung, ovarian, and cervical.
Purpose of the Study:
- To investigate GPP130 as a substrate for proprotein convertase 7 (PC7; PCSK7).
- To analyze the impact of GPP130 cleavage by PC7 and/or Furin on cancer cell proliferation.
- To explore the cellular biology and biochemical characterization of GPP130 in cancer progression.
Main Methods:
- Proteomics screening to identify potential GPP130 substrates.
- Bioinformatic analysis of GPP130/GOLIM4 gene amplification in cancer using cBioPortal.
- Cell-based assays using A549 lung cancer cells to study endogenous and overexpressed GPP130.
- Analysis of GPP130 cleavage by PC7 and/or Furin and its effect on cellular growth.
Main Results:
- GPP130 was identified as a potential substrate of PC7.
- GPP130 gene amplification is observed in multiple cancer types.
- GPP130 enhances proliferation in A549, SKOV3, and HeLa cancer cell lines.
- Cleavage of GPP130 by PC7 and/or Furin generates N-terminal membrane-bound and C-terminal secreted fragments, further enhancing proliferation.
Conclusions:
- GPP130 is a novel substrate for PC7 and Furin, playing a significant role in cancer cell proliferation.
- Cleavage and shedding of GPP130 by PC7/Furin modulate its proliferative activity, potentially contributing to lung cancer progression.
- This study elucidates the cell biology of GPP130 and its biochemical regulation in cancer.
