Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis
Open accessAbstract
After internalization, transmembrane receptors (TMRs) are typically recycled back to the cell surface or targeted for degradation. Efficient TMR trafficking is critical for regulation of several processes, including signal transduction pathways, development, and disease. Here, we determined that trafficking of the angiogenic receptor neuropilin-1 (NRP-1) is abrogated by the liver kinase B1 (LKB1), a serine-threonine kinase of the calcium calmodulin family. We found that aberrant NRP-1 expression in tumor cells from patients with lung adenocarcinoma is associated with decreased levels of LKB1. In cultured lung cells, LKB1 accentuated formation of a complex between NRP-1 and RAB7 in late endosomes. LKB1 specifically bound GTP-bound RAB7, but not a dominant-negative GDP-bound form of RAB7, promoting rapid transfer and lysosome degradation of NRP-1. siRNA-mediated depletion of RAB7 disrupted the transfer of NRP-1 to the lysosome, resulting in recovery of the receptor as well as increased tumor growth and angiogenesis. Together, our findings indicate that LKB1 functions as a RAB7 effector and suppresses angiogenesis by promoting the cellular trafficking of NRP-1 from RAB7 vesicles to the lysosome for degradation. Furthermore, these data suggest that LKB1 and NRP-1 have potential as therapeutic targets for limiting tumorigenesis.
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In the Keap1Fl/Fl;PtenFl/Fl GEMM, deleting both Keap1 and Pten produced immunologically cold tumors resembling those with Lkb1 mutation.
“In a conditional GEMM of LUAD (Keap1Fl/Fl;PtenFl/Fl), co-deletion of Keap1 and Pten resulted in immunologically cold tumors, akin to Lkb1-mutant NSCLC141.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [141]
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Functions of Neuropilins in Wiring the Nervous System and Their Role in Neurological Disorders
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Rab7a is required to degrade select blood-brain barrier junctional proteins after ischemic strokePreprint
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- Authors
- Okon, I. S., Coughlan, K. A., Zhang, C., Moriasi, C., Ding, Y., Song, P., Zhang, W., Li, G., & Zou, M.-H.
- Affiliations
- University of Oklahoma (US)
- Shandong University (CN)
- Corresponding author
- Zou, Ming-Hui
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-09-02
- Volume
- 124
- Issue
- 10
- Pages
- 4590-4602
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4191012
- OpenAlex
- W2073594821
- Cited by
- 52
- References
- 56
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 5 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 3 · 2017: 6 · 2016: 5 · 2015: 2
- FWCI
- 2.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL080499, HL074399)
- National Institute on Aging (AG047776, R01AG047776)
- National Heart, Lung, and Blood Institute (HL-105157, R01HL105157, HL 079584, R01HL079584, HL110488, HL-080499, HL096032, HL074399, R01HL074399, R01HL080499, HL-089920, R01HL110488, R01HL089920, R01HL096032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- LKB1, neuropilin-1, Rab7, angiogenesis, receptor degradation, lysosomal degradation, late endosomes, receptor trafficking, lung adenocarcinoma, tumor growth, therapeutic target
- MeSH terms
- Adenocarcinoma of Lung, rab7 GTP-Binding Proteins, AMP-Activated Protein Kinase Kinases, Adenocarcinoma, Aged, Animals, Cell Membrane, Female, Humans, Lung, Lung Neoplasms, Lysosomes, Male, Middle Aged, Mutation, Neovascularization, Pathologic, Signal Transduction, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Protein Serine-Threonine Kinases, rab GTP-Binding Proteins, RNA Interference, RNA, Small Interfering, Neuropilin-1, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Mice, AMP-Activated Protein Kinases
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