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Inhibiting S-palmitoylation arrests metastasis by relocating Rap2b from plasma membrane in colorectal cancer

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机构： [1]The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China [2]Institute of Psychiatry and Neuroscience, Xinxiang Key Laboratory of Protein Palmitoylation and MajorHuman Diseases, Xinxiang Medical University, Xinxiang, China [3]Lankao County Central Hospital, Lankao, China [4]Henan Health Commission Key Laboratory of GastrointestinalCancer Prevention and Treatment, Xinxiang Medical University, Xinxiang, China [5]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan Universityand National Collaborative Innovation Center, Chengdu, China [6]College of Pharmacy, Xinxiang Medical University, Xinxiang, China [7]School of Pharmacy, China PharmaceuticalUniversity, Nanjing, China

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Rap2b, a proto-oncogene upregulated in colorectal cancer (CRC), undergoes protein S-palmitoylation at specific C-terminus sites (C176/C177). These palmitoylation sites are crucial for Rap2b localization on the plasma membrane (PM), as mutation of C176 or C177 results in cytosolic relocation of Rap2b. Our study demonstrates that Rap2b influences cell migration and invasion in CRC cells, independent of proliferation, and this activity relies on its palmitoylation. We identify ABHD17a as the depalmitoylating enzyme for Rap2b, altering PM localization and inhibiting cell migration and invasion. EGFR/PI3K signaling regulates Rap2b palmitoylation, with PI3K phosphorylating ABHD17a to modulate its activity. These findings highlight the potential of targeting Rap2b palmitoylation as an intervention strategy. Blocking the C176/C177 sites using an interacting peptide attenuates Rap2b palmitoylation, disrupting PM localization, and suppressing CRC metastasis. This study offers insights into therapeutic approaches targeting Rap2b palmitoylation for the treatment of metastatic CRC, presenting opportunities to improve patient outcomes.© 2024. The Author(s).

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出版当年[2023]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

最新[2023]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

第一作者：

第一作者机构： [1]The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China [2]Institute of Psychiatry and Neuroscience, Xinxiang Key Laboratory of Protein Palmitoylation and MajorHuman Diseases, Xinxiang Medical University, Xinxiang, China

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通讯作者：

通讯机构： [1]The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China [2]Institute of Psychiatry and Neuroscience, Xinxiang Key Laboratory of Protein Palmitoylation and MajorHuman Diseases, Xinxiang Medical University, Xinxiang, China [4]Henan Health Commission Key Laboratory of GastrointestinalCancer Prevention and Treatment, Xinxiang Medical University, Xinxiang, China

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