AUTHOR=Zhao Haile , Gezi Gezi , Tian Xiaoxia , Jia Peijun , Morigen Morigen , Fan Lifei 

TITLE=Lysophosphatidic Acid–Induced EGFR Transactivation Promotes Gastric Cancer Cell DNA Replication by Stabilizing Geminin in the S Phase

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.706240

DOI=10.3389/fphar.2021.706240

ISSN=1663-9812

ABSTRACT=Geminin, an inhibitor of the DNA replication licensing factor chromatin licensing and DNA replication factor (Cdt) 1, is essential for the maintenance of genomic integrity. As a multifunctional protein, geminin is also involved in tumor progression but the molecular details are largely unknown. Here we found that lysophosphatidic acid (LPA)-induced up-regulation of geminin was specific to gastric cancer cells. LPA acted via LPA receptor (LPAR) 3 and matrix metalloproteinases (MMPs) signaling to transactivate epidermal growth factor receptor (EGFR) (Y1173) and thereby stabilize geminin expression level during S phase. LPA also induced the expression of deubiquitinating protein (DUB) 3, which prevented geminin degradation. These results reveal a novel mechanism underlying gastric cancer progression that involves the regulation of geminin stability by LPA-induced EGFR transactivation, and provide potential targets for signaling pathway- and tumor cell-specific inhibitors.