The Akt–mTORC1 pathway mediates Axl receptor tyrosine kinase-induced mesangial cell proliferation,Journal of Leukocyte Biology

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The Akt–mTORC1 pathway mediates Axl receptor tyrosine kinase-induced mesangial cell proliferation
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2021-07-04 , DOI: 10.1002/jlb.2a1220-850rrr
Yuxuan Zhen ₁ , Tracy L McGaha _{2,

3} , Fred D Finkelman _{1,

4} , Wen-Hai Shao ₁

Affiliation

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.

中文翻译：

Akt-mTORC1 通路介导 Axl 受体酪氨酸激酶诱导的系膜细胞增殖

肾小球肾炎 (GN) 是许多肾脏疾病的重要病理特征，通常以系膜细胞增殖为特征。我们和其他人之前已经证明，TAM 家族受体酪氨酸激酶 Axl、Mer 和 Tyro-3 有助于细胞存活、增殖、迁移和凋亡细胞 (AC) 的清除；Axl 通过促进系膜细胞增殖对 GN 起作用；并且 Axl 的小分子抑制改善了小鼠肾毒性血清诱导的 GN。我们现在表明，刺激肾系膜细胞 Axl 会导致细胞内 Ca ^{2+的适度增加}并激活 NF-κB、mTOR 和含有 mTOR 的 mTORC1 复合物，后者使核糖体蛋白 S6 磷酸化。Akt 激活的 Axl 诱导是相互依赖的 NF-κB 和 mTOR 激活的上游。Axl 诱导的 NF-κB 活化导致 Bcl-xl 上调。Axl 在介导系膜细胞对 AC 的吞噬作用方面比 Mer 更重要，但在介导腹膜巨噬细胞对 AC 的吞噬作用方面不如 Mer 重要。总之，我们的数据表明 Axl 可能通过激活 NF-κB 和 mTORC1 介导 ACs 的系膜细胞吞噬作用并促进系膜细胞增殖。

更新日期：2021-07-04

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