Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer
Abstract Pancreatic cancer (PC) is prone to distant metastasis in the early stage, which is attributed to the strong migration ability of tumor cells. Focal adhesion turnover is essential for cancer cell metastasis, and the integrin recycling process is a key activation pathway for focal adhesion de...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05338-y |
| _version_ | 1811335073798029312 |
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| author | Zhiwei He Jie Wang Jian Xu Xueyi Jiang Xinyuan Liu Jianxin Jiang |
| author_facet | Zhiwei He Jie Wang Jian Xu Xueyi Jiang Xinyuan Liu Jianxin Jiang |
| author_sort | Zhiwei He |
| collection | DOAJ |
| description | Abstract Pancreatic cancer (PC) is prone to distant metastasis in the early stage, which is attributed to the strong migration ability of tumor cells. Focal adhesion turnover is essential for cancer cell metastasis, and the integrin recycling process is a key activation pathway for focal adhesion depolymerization. To identify the key motor protein involving in the integrin β1 recycling, we screened kinesin proteins involved in integrin β1 recycling using a kinesin family siRNA library and identified kinesin family 15 (KIF15) as a key regulator. KIF15 was upregulated in metastasis PC tissues and promoted PC cell migration and invasion. We identified KIF15 as a key component mediating integrin β1/FAK signaling that accelerated FA disassembly in a FAK-Y397-dependent manner. KIF15 recruited PI3K-C2α to promote integrin β1/FAK signaling and FA disassembly in a RAB11A-dependent manner. The C-terminal tail of KIF15 is required for the PI3K-C2α interaction and RAB11A activation. In addition, we also found that SIRT1-mediated acetylation of KIF15 is essential for KIF15 phosphorylation, which is the key activation event in motor protein function. Together, these findings indicate that KIF15 interacts with PI3K-C2α to promote FA turnover in PC cells by controlling the endosome recycling of integrin β1 in a SIRT1 acetylation modification-dependent manner, eventually promoting focal adhesions turnover and distant metastasis in PC. |
| first_indexed | 2024-04-13T17:18:38Z |
| format | Article |
| id | doaj.art-827f06d94dfa49559a78773d15a4a92e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T17:18:38Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-827f06d94dfa49559a78773d15a4a92e2022-12-22T02:38:04ZengNature Publishing GroupCell Death and Disease2041-48892022-10-01131011310.1038/s41419-022-05338-yDynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancerZhiwei He0Jie Wang1Jian Xu2Xueyi Jiang3Xinyuan Liu4Jianxin Jiang5Department of Hepatic-Biliary Surgery, Renmin Hospital of Wuhan UniversityDepartment of Hepatic-Biliary Surgery, Renmin Hospital of Wuhan UniversityDepartment of Hepatic-Biliary Surgery, Renmin Hospital of Wuhan UniversityDepartment of Hepatic-Biliary Surgery, Renmin Hospital of Wuhan UniversityDepartment of Hepatic-Biliary Surgery, Renmin Hospital of Wuhan UniversityDepartment of Hepatic-Biliary Surgery, Renmin Hospital of Wuhan UniversityAbstract Pancreatic cancer (PC) is prone to distant metastasis in the early stage, which is attributed to the strong migration ability of tumor cells. Focal adhesion turnover is essential for cancer cell metastasis, and the integrin recycling process is a key activation pathway for focal adhesion depolymerization. To identify the key motor protein involving in the integrin β1 recycling, we screened kinesin proteins involved in integrin β1 recycling using a kinesin family siRNA library and identified kinesin family 15 (KIF15) as a key regulator. KIF15 was upregulated in metastasis PC tissues and promoted PC cell migration and invasion. We identified KIF15 as a key component mediating integrin β1/FAK signaling that accelerated FA disassembly in a FAK-Y397-dependent manner. KIF15 recruited PI3K-C2α to promote integrin β1/FAK signaling and FA disassembly in a RAB11A-dependent manner. The C-terminal tail of KIF15 is required for the PI3K-C2α interaction and RAB11A activation. In addition, we also found that SIRT1-mediated acetylation of KIF15 is essential for KIF15 phosphorylation, which is the key activation event in motor protein function. Together, these findings indicate that KIF15 interacts with PI3K-C2α to promote FA turnover in PC cells by controlling the endosome recycling of integrin β1 in a SIRT1 acetylation modification-dependent manner, eventually promoting focal adhesions turnover and distant metastasis in PC.https://doi.org/10.1038/s41419-022-05338-y |
| spellingShingle | Zhiwei He Jie Wang Jian Xu Xueyi Jiang Xinyuan Liu Jianxin Jiang Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer Cell Death and Disease |
| title | Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer |
| title_full | Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer |
| title_fullStr | Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer |
| title_full_unstemmed | Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer |
| title_short | Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer |
| title_sort | dynamic regulation of kif15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer |
| url | https://doi.org/10.1038/s41419-022-05338-y |
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