Lysosomal protein transmembrane 5 promotes lung-specific metastasis by regulating BMPR1A lysosomal degradation

Bo Jiang, Xiaozhi Zhao, Wei Chen, Wenli Diao, Meng Ding, Haixiang Qin, Binghua Li, Wenmin Cao, Wei Chen, Yao Fu, Kuiqiang He, Jie Gao, Mengxia Chen, Tingsheng Lin, Yongming Deng, Chao Yan () and Hongqian Guo ()
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Bo Jiang: Nanjing University
Xiaozhi Zhao: Nanjing University
Wei Chen: Nanjing University
Wenli Diao: Nanjing University
Meng Ding: Nanjing University
Haixiang Qin: Nanjing University
Binghua Li: the Affiliated Hospital of Nanjing University Medical School
Wenmin Cao: Nanjing University
Wei Chen: Nanjing University
Yao Fu: Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School
Kuiqiang He: Nanjing University
Jie Gao: Nanjing University
Mengxia Chen: Nanjing University
Tingsheng Lin: Nanjing University
Yongming Deng: Nanjing University
Chao Yan: Nanjing University
Hongqian Guo: Nanjing University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Organotropism during cancer metastasis occurs frequently but the underlying mechanism remains poorly understood. Here, we show that lysosomal protein transmembrane 5 (LAPTM5) promotes lung-specific metastasis in renal cancer. LAPTM5 sustains self-renewal and cancer stem cell-like traits of renal cancer cells by blocking the function of lung-derived bone morphogenetic proteins (BMPs). Mechanistic investigations showed that LAPTM5 recruits WWP2, which binds to the BMP receptor BMPR1A and mediates its lysosomal sorting, ubiquitination and ultimate degradation. BMPR1A expression was restored by the lysosomal inhibitor chloroquine. LAPTM5 expression could also serve as an independent predictor of lung metastasis in renal cancer. Lastly, elevation of LAPTM5 expression in lung metastases is a common phenomenon in multiple cancer types. Our results reveal a molecular mechanism underlying lung-specific metastasis and identify LAPTM5 as a potential therapeutic target for cancers with lung metastasis.

Date: 2022
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DOI: 10.1038/s41467-022-31783-6

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