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CDCP1 通过整合Src 和 Met 信号促进代偿性肾生长。

CDCP1 promotes compensatory renal growth by integrating Src and Met signaling.

机构信息

Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Kanagawa, Japan.

出版信息

Life Sci Alliance. 2021 Feb 11;4(4). doi: 10.26508/lsa.202000832. Print 2021 Apr.

DOI:10.26508/lsa.202000832
PMID:33574034
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7893822/
Abstract

Compensatory growth of organs after loss of their mass and/or function is controlled by hepatocyte growth factor (HGF), but the underlying regulatory mechanisms remain elusive. Here, we show that CUB domain-containing protein 1 (CDCP1) promotes HGF-induced compensatory renal growth. Using canine kidney cells as a model of renal tubules, we found that HGF-induced temporal up-regulation of Src activity and its scaffold protein, CDCP1, and that the ablation of CDCP1 robustly abrogated HGF-induced phenotypic changes, such as morphological changes and cell growth/proliferation. Mechanistic analyses revealed that up-regulated CDCP1 recruits Src into lipid rafts to activate STAT3 associated with the HGF receptor Met, and activated STAT3 induces the expression of matrix metalloproteinases and mitogenic factors. After unilateral nephrectomy in mice, the Met-STAT3 signaling is transiently up-regulated in the renal tubules of the remaining kidney, whereas CDCP1 ablation attenuates regenerative signaling and significantly suppresses compensatory growth. These findings demonstrate that CDCP1 plays a crucial role in controlling compensatory renal growth by focally and temporally integrating Src and Met signaling.

摘要

器官在失去其质量和/或功能后的代偿性生长受肝细胞生长因子（HGF）的控制，但潜在的调节机制仍不清楚。在这里，我们发现 CUB 结构域蛋白 1（CDCP1）促进 HGF 诱导的代偿性肾脏生长。使用犬肾细胞作为肾小管模型，我们发现 HGF 诱导 Src 活性及其支架蛋白 CDCP1 的时间上调，并且 CDCP1 的消融强烈阻断 HGF 诱导的表型变化，例如形态变化和细胞生长/增殖。机制分析表明，上调的 CDCP1 将 Src 募集到脂筏中以激活与 HGF 受体 Met 相关的 STAT3，而激活的 STAT3 诱导基质金属蛋白酶和有丝分裂因子的表达。在小鼠单侧肾切除术后，剩余肾脏中的肾小管中 Met-STAT3 信号短暂上调，而 CDCP1 消融减弱再生信号并显著抑制代偿性生长。这些发现表明，CDCP1 通过局部和暂时整合 Src 和 Met 信号在控制代偿性肾生长中发挥关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/f886c2769206/LSA-2020-00832_FigS13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/bf1b96114edc/LSA-2020-00832_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/38f0a5b75f37/LSA-2020-00832_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/b40f04c4d363/LSA-2020-00832_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/bd46e27971ac/LSA-2020-00832_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/f7846d939316/LSA-2020-00832_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/3d88cc2d8005/LSA-2020-00832_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/94a1d4ad68df/LSA-2020-00832_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/3e7143637c96/LSA-2020-00832_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/e05e3d2b9c92/LSA-2020-00832_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/e281c9a3b300/LSA-2020-00832_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/3bd7149b27be/LSA-2020-00832_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/6223063de91e/LSA-2020-00832_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/de2ae2251423/LSA-2020-00832_FigS8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/da1a1999c9af/LSA-2020-00832_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/0c665182aa03/LSA-2020-00832_FigS10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/fc10bda53828/LSA-2020-00832_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/f435ac45aee7/LSA-2020-00832_FigS11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/2bd245171ff7/LSA-2020-00832_FigS12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/f886c2769206/LSA-2020-00832_FigS13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/bf1b96114edc/LSA-2020-00832_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/38f0a5b75f37/LSA-2020-00832_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/b40f04c4d363/LSA-2020-00832_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/bd46e27971ac/LSA-2020-00832_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/f7846d939316/LSA-2020-00832_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/3d88cc2d8005/LSA-2020-00832_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/94a1d4ad68df/LSA-2020-00832_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/3e7143637c96/LSA-2020-00832_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/e05e3d2b9c92/LSA-2020-00832_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/e281c9a3b300/LSA-2020-00832_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/3bd7149b27be/LSA-2020-00832_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/6223063de91e/LSA-2020-00832_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/de2ae2251423/LSA-2020-00832_FigS8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/f54434a089db/LSA-2020-00832_FigS9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/da1a1999c9af/LSA-2020-00832_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/0c665182aa03/LSA-2020-00832_FigS10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/fc10bda53828/LSA-2020-00832_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/f435ac45aee7/LSA-2020-00832_FigS11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/2bd245171ff7/LSA-2020-00832_FigS12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1893/7893822/f886c2769206/LSA-2020-00832_FigS13.jpg

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