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The Akt-mTORC1 pathway mediates Axl receptor tyrosine kinase-induced mesangial cell proliferation.

ABSTRACT: Glomerulonephritis (GN), an important pathologic feature of many renal diseases, is frequently characterized by mesangial cell proliferation. We and others have previously shown that the TAM family receptor tyrosine kinases Axl, Mer, and Tyro-3 contribute to cell survival, proliferation, migration, and clearance of apoptotic cells (ACs); that Axl contributes to GN by promoting mesangial cell proliferation; and that small molecule inhibition of Axl ameliorates nephrotoxic serum-induced GN in mice. We now show that stimulation of renal mesangial cell Axl causes a modest increase in intracellular Ca²⁺ and activates NF-κB, mTOR, and the mTOR-containing mTORC1 complex, which phosphorylates the ribosomal protein S6. Axl-induction of Akt activation is upstream of NF-κB and mTOR activation, which are mutually codependent. Axl-induced NF-κB activation leads to Bcl-xl up-regulation. Axl is more important than Mer at mediating AC phagocytosis by mesangial cells, but less important than Mer at mediating phagocytosis of ACs by peritoneal macrophages. Taken together, our data suggest the possibility that Axl mediates mesangial cell phagocytosis of ACs and promotes mesangial cell proliferation by activating NF-κB and mTORC1.

SUBMITTER: Zhen Y

PROVIDER: S-EPMC9328168 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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The Akt-mTORC1 pathway mediates Axl receptor tyrosine kinase-induced mesangial cell proliferation.

Zhen Yuxuan Y McGaha Tracy L TL Finkelman Fred D FD Shao Wen-Hai WH

Journal of leukocyte biology 20210704 3

Glomerulonephritis (GN), an important pathologic feature of many renal diseases, is frequently characterized by mesangial cell proliferation. We and others have previously shown that the TAM family receptor tyrosine kinases Axl, Mer, and Tyro-3 contribute to cell survival, proliferation, migration, and clearance of apoptotic cells (ACs); that Axl contributes to GN by promoting mesangial cell proliferation; and that small molecule inhibition of Axl ameliorates nephrotoxic serum-induced GN in mice ...[more]

PMID: 34218441

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Project description:BackgroundReceptor tyrosine kinase AXL has been found to be highly expressed in osteosarcoma and positively associated with poor prognosis. There are tumor groups with high or low AXL expression, which had different capabilities of invading vessels and forming distal metastases. Exosome-transmitted lncRNA may be transferred intercellularly to promote tumor cells' proliferation and invasion.MethodsExosomes were detected by electron microscopy, particle size analysis, and western blotting. High-throughput sequencing helped to find the highest differentially expressed lncRNA in AXL-associated exosomes. Clone formation, wound healing, transwell assay, and xenograft model in nude mice were performed to evaluate cells' proliferation, migration, and invasion in vitro and in vivo. Lentiviral transfection was used to up- or down-regulate the lncRNA levels in cell lines. Luciferase reporter assay and RNA FISH etchelped to indicate the molecular mechanisms. The results in the cell lines were proved in the osteosarcoma tissues with clinical analysis.ResultsThe exosomes derived from donor cells with high AXL expression could promote the proliferation and invasion and upregulate AXL expression of the receiver cells with low AXL. Linc00852 was the highest differentially expressed lncRNA in AXL-associated exosomes and was also regulated by AXL expression. Although the mechanisms of linc00852 in nucleus were unrevealed, it could upregulate AXL expression partly by competitively binding to miR-7-5p. The AXL-exosome-linc00852-AXL positive feedback loop might exist between the donor cells and the receiver cells. Clinically, linc00852 was significantly highly expressed in osteosarcoma tissues and positively associated with tumor volumes and metastases, which was also obviously related with AXL mRNA expression.ConclusionAXL-associated exosomal linc00852 up-regulated the proliferation, migration, and invasion of osteosarcoma cells, which would be considered as a new tumor biomarker and a special therapeutic target for osteosarcoma.

Dataset Information

The Akt-mTORC1 pathway mediates Axl receptor tyrosine kinase-induced mesangial cell proliferation.

Publications

The Akt-mTORC1 pathway mediates Axl receptor tyrosine kinase-induced mesangial cell proliferation.

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