# Shedding of GPP130 by PC7 and Furin: Potential Implication in Lung Cancer Progression
###### Abstract  
From a previously performed proteomics screen, GPP130, or Golgi phosphoprotein of 130 kDa, was identified as a potential substrate of the proproticen 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. G 2025, 26, 6164 2025 26, 616  
PCSK9, are highly successful in the treatment of hypercholesterolemia and beyond [10; 11]. The physiological roles of the ubiquitously expressed PC7 (gene PCSK7), the seventh member of the family [12], remained obscure for a long time--however, very recently, [PERSON] et al. [13] demonstrated that in mice, liver PC7 plays a critical role in enhancing apolipoprotein B (apoB) levels, and the silencing of its expression provided a promising treatment for diet-induced metabolic dysfunction-associated steatohepatitis liver disease (MASLD), a devastating pathology that affects at least 25% the population worldwide [14]. To identify novel PC7 substrates, we performed a quantitative proteomics screen targeting N-glycosated polypeptides secreted by hepatic HuH7 cells overexpressing PC7. This analysis revealed two type-II transmembrane proteins--cancer susceptibility candidate 4 (CASC4) and Golgi phosphoprotein 130 (GPP130)--that are shed into soluble forms by PC7 and/or Furin (Figure 1A) [4]. The latter study revealed that CASC4, especially its PC7/Furin-cleaved N-terminal membrane-bound fragment, enhanced the migration and invasion of triple-negative MDA-MB-231 breast cancer cells [4]. Our analysis from the cBioPortal for Cancer Genomics database has shown that the expression of the genes coding for CASC4 and GPP130 are differentially modified in various cancers (Figure 1B). However, GPP130 and its shedding were not functionally characterized, especially since GPP130 expression is amplified in up to 35% of patients with lung cancer and >10% in head-and-neck cancer patients (Figure 1B). Herein, we have filled the knowledge gap on GPP130 and additionally compared the properties of GPP130 to those of CASC4. GPP130 is a type-II transmembrane Golgi protein comprising a short cytosolic tail, a 20-aa transmembrane domain, and a luminal domain that contains determinants guiding its trafficking itinerary [15; 16]. Hence, GPP130 is able to traffic from the cis-Golgi to the plasma membrane and back via the TGN38/46 bypass pathway [17; 18]. Further investigations demonstrated that GPP130 traffics to early endosomes where it binds the Shiga toxin internalized into cell surface endosomes, and the complex is then sorted back to the Golgi and retrograde transported to the endoplasmic reticulum (ER) to exert its cytotoxic effects [19; 20].