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Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis
Imoh S. Okon, … , Guangpu Li, Ming-Hui Zou
Imoh S. Okon, … , Guangpu Li, Ming-Hui Zou
Published October 1, 2014; First published September 2, 2014
Citation Information: J Clin Invest. 2014;124(10):4590-4602. https://doi.org/10.1172/JCI75371.
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Categories: Research Article Vascular biology

Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis

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Abstract

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.

Authors

Imoh S. Okon, Kathleen A. Coughlan, Cheng Zhang, Cate Moriasi, Ye Ding, Ping Song, Wencheng Zhang, Guangpu Li, Ming-Hui Zou

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Figure 4

Hypoxia promotes LKB1 cytoplasmic distribution.

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Hypoxia promotes LKB1 cytoplasmic distribution.
(A) Immunofluorescence a...
(A) Immunofluorescence analysis of LKB1 (red) and DAPI (blue) under normoxic or hypoxic conditions in H1792 cells. Scale bars: 5 μm. (B) The nuclear/cytoplasmic ratio of LKB1 immunofluorescence in A was quantified; mean ± SD is shown (n = 10). (C) Immunofluorescence analysis of wild-type LKB1 (green), the constitutively nuclear-localized SL-26 mutant (green), and DAPI (blue) under normoxia in transfected A549 cells. Scale bars: 5 μm. (D and E) Cytosolic and nuclear fractions of A549 cells transiently transfected with wild-type LKB1 or SL-26 were blotted for NRP-1, LKB1, and markers for different cell fractions. SL-26 possesses an EGFP tag. Mean ± SD is shown (n = 3). (F) NRP-1 pulldown in A549 cells using the LKB1 mutants SL-26, D194A (kinase inactive), and S428A (point mutation at phosphorylation site 428). Interaction of NRP-1 and LKB1 were assessed in immunoprecipitated samples. (G) Reverse LKB1 pulldown and immunoblotting with NRP-1 and LKB1 antibodies. **P < 0.01, ***P < 0.001.
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