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

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

doi:10.1172/jci75371

Cited by 46 publications

(58 citation statements)

References 55 publications

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“…Embryonic lethality caused by vascular defects is a common phenotype in mice with whole body homozygous ablation of LKB1 [22], endothelium-restricted deletion of LKB1 [23], or partial endothelial-deletion of LKB1 [39, 40]. In matured blood vessels, endothelial overexpression of LKB1 inhibits VEGF signaling [41], enhances senescence [10, 12], prevents proliferation and induces apoptosis [42]. Here, the results suggest that in aged arteries, accumulation of acetylated LKB1 in the endothelium stimulates the proliferation of surrounding vascular smooth muscle cells and triggers adverse arterial remodeling.…”

Section: Discussionmentioning

confidence: 99%

Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1

et al. 2016

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Aims-SIRT1 exerts potent activity against cellular senescence and vascular ageing. By decreasing LKB1 protein levels, it promotes the survival and regeneration of endothelial cells. The present study aims to investigate the molecular mechanisms underlying SIRT1-mediated LKB1 degradation for the prevention of vascular ageing.Methods and Results-Co-immunoprecipitation assay demonstrated that SIRT1, via its amino-terminus, binds to the DOC domain of HERC2 [HECT and RLD domain containing E3 ubiquitin protein ligase 2], which then ubiquitinates LKB1 in the nuclear compartment of endothelial cells. Site-directed mutagenesis revealed that acetylation at lysine (K) 64 of LKB1 triggers the formation of SIRT1/HERC2/LKB1 protein complex and subsequent proteasomal degradation. In vitro cellular studies suggested that accumulation of acetylated LKB1 in the nucleus leads to endothelial activation, in turn stimulating the proliferation of vascular smooth muscle cells and the production of extracellular matrix proteins. Chromatin immunoprecipitation quantitative PCR confirmed that acetylated LKB1 interacts with and activates TGFβ1 promoter, which is inhibited by SIRT1. Knocking down either SIRT1 or HERC2 results in an increased association of LKB1 with the positive regulatory elements of TGFβ1 promoter. In mice without endothelial nitric oxide synthase, selective overexpression of human SIRT1 in endothelium prevents hypertension and age-related adverse arterial remodeling. Lentiviral-mediated knockdown of HERC2 abolishes the beneficial effects of endothelial SIRT1 on both arterial remodeling and arterial blood pressure control.Conclusion-By downregulating acetylated LKB1 protein via HERC2, SIRT1 fine-tunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis.

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Section: Discussionmentioning

confidence: 99%

Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1

et al. 2016

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“…There is ample evidence that deregulation of the LKB1 signaling pathway appears to play a major role in tumor pathogenesis, since it facilitates malignant development through suppression of cell apoptosis and growth arrest (27)(28)(29)(30). To investigate the oncogenic state of the L02 cell line, functional assays were carried out including evaluation of the clonogenicity and tumor-initiating potential.…”

Section: Discussionmentioning

confidence: 99%

“…anchorage-independent growth in soft agar is one of the hallmark characteristics of cellular transformation and uncontrolled cell growth, with normal cells typically not capable of growth in semi-solid matrices (26). Recent studies have provided compelling evidence that loss of LKB1 activity is a critical step in oncogenesis (27)(28)(29)(30). To explore the oncogenic potential of LKB1-deficient L02 cells, a soft agar colony formation assay was carried out.…”

Section: Ectopic Lkb1 Expression Blocks Rb Phosphorylation In the L02mentioning

confidence: 99%

LKB1 expression reverses the tumorigenicity of L02 cells

Liang

Gao

et al. 2016

Oncology Reports

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Abstract. The tumor-suppressor liver kinase B1 (LKB1), a highly conserved and ubiquitously expressed protein kinase, plays a critical role in tumorigenesis. In the present study, we revealed that human hepatic L02 cells had severely impaired endogenous LKB1 expression as gauged by western blot, northern blot and RT-PCR analyses. Stable ectopic expression of LKB1 in L02 cells resulted in decreased cell growth, hypophosphorylation of Rb, and marked attenuation of colony formation on soft agar. Inoculation of L02 cells into immunocompromised mice resulted in the development of subcutaneous tumors, which could be completely abrogated by ectopic LKB1 expression. The tumors that formed in the mouse model recapitulated the histopathological features of hepatocellular carcinoma under the microscope. Our results jointly suggest that severely compromised endogenous LKB1 expression in the L02 cell line may confer to L02 cells tumorinitiating capacities in vivo and in vitro, and ectopic LKB1 expression antagonizes the tumorigenic properties of L02 cells. Our findings imply that caution may be needed to interpret the results obtained on the widely used human hepatic L02 cell line. The L02 cell line may be a new model to define the cellular mechanisms of liver transformation, and to unravel the molecular mechanisms underlying the growth suppressive effect of LKB1.

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“…Defective trafficking, internalization or degrardation of transmembrane receptors (TMRs) result in perturbed activation of signaling networks, which play essential roles in disease initiation or accentuation. In our recent study, we found that liver kinase B1 (LKB1), a calcium–calmodulin family member abrogated neuropilin-1 (NRP-1) protein in lung cancer clinical specimens and cell lines [ 1 ]. Surprisingly, this observation was reminiscent to our previous finding in which LKB1 attenuated the activation of a repertoire of receptor tyrosine kinases (RTKs), including EGFR, ErbB2, HGFR (c-Met) and EphA2 [ 2 ].…”

mentioning

confidence: 99%

“…The regulation of TMRs by LKB1 appears to be a recurring pattern in cancer cells but occur via different mechanisms. Unlike LKB1-mediated dephosphorylation of RTKs via accentuation of selected phosphatase activity, NRP-1 attenuation was promoted by LKB1-RAB7 GTPase complex [ 1 , 2 ]. We demonstrated for the first time that LKB1 is a RAB7 effector and suppresses tumor angiogenesis by promoting cellular trafficking of NRP-1 from RAB7 vesicles to the lysosome for degradation.…”

mentioning

confidence: 99%