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

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.

• Authors: 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, Hongqian Guo
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 4141 (07 16 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35842443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Membrane Proteins
• lysosomal proteins
• WWP2 protein, human
• Ubiquitin-Protein Ligases
• BMPR1A protein, human
• Bone Morphogenetic Protein Receptors, Type I

Topics

• Bone Morphogenetic Protein Receptors, Type I (genetics, metabolism)
• Humans
• Kidney Neoplasms (metabolism)
• Lung Neoplasms (genetics, metabolism)
• Lysosomes (metabolism)
• Membrane Proteins (genetics, metabolism)
• Ubiquitin-Protein Ligases (metabolism)