腎纖維化是急性腎損傷（AKI）對慢性腎臟病（CKD）的重要標誌，而據報導轉化生長因子-β1（TGF-β1）誘導的上皮-間質轉化（EMT）有助於腎纖維化的發展。表皮生長因子（EGF）可以促進細胞生長，細胞增殖和細胞分化。在許多文獻中，我們可以發現EGF和TGF-β訊息途徑之間的關聯是眾所周知的。微囊蛋白(caveolin-1，Cav-1)是小窩(caveolae)的主要外殼蛋白並與信號轉導的調控有關，儘管先前已被報導Cav-1可以抑制TGF-β在腎上皮細胞中的表達。然而，Cav-1調節TGF-β1和EGF基因表達以及TGF-β/Smad3（典型）和非Smad3（非典型）如EGF / ERK信號傳導的詳細分子機制仍不清楚。這項研究的目的是探討TGF-β與EGF之間Cav-1的交叉調節作用。犬腎臟上皮細胞(MDCK) 中穩定Cav-1的過度表達或敲除被使用於本研究。另一方面，各種Cav-1突變體（Y14D、Y14F和CSDmut）也在MDCK細胞中過度表達，以研究酪氨酸14的磷酸化或Cav-1支架結構域（CSD）是否參與TGF-β或是EGF信號的調控。通過分別模擬磷酸化或非磷酸化的氨基酸酪氨酸14來產生Y14D和Y14F。並產生了Cav-1支架結構域（CSD）突變(F92A，T95A）成為CSD失活形式。Smad3和ERK2核易位的共軛聚焦成像TGF-β和EGF下游蛋白之磷酸化用於評估TGF-β1和EGF信號的激活。對於Cav-1通過TGF-β和EGF處理對TGF-β和EGF信號轉導的影響，我們發現Cav-1的過表達抑制了Smad3和ERK2的活化和核易位，而Cav-1的敲落增加了Smad3和ERK2激活和核易位。在TGF-β與EGF之間的交互作用中，Cav-1的過度表達通過TGF-β處理抑制了ERK2活化和核易位。但是，Cav-1的過度表達反而會通過EGF處理促進Smad3活化和核易位。此外，我們透過MβCD與CSD-peptide處理來影響Cav-1功能以及與內生性CSD競爭證實了這一結果。此外，Y14D和CSDmut突變體而不是藉由Y14F抑制Smad3激活和核易位。因此，我們可以推斷出Cav-1具有抑制作用，而Cav-1的Y14磷酸化在抑制TGF-β和EGF信號傳導中起著重要的作用。

Renal fibrosis is an important sign of acute kidney injury from chronic kidney disease. Transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) has been reported to contribute to the development of kidney fibrosis. Another growth factor, epidermal growth factor (EGF) can promote cell growth, cell proliferation and cell differentiation. Many studies have reported the association between EGF and TGF-β signal pathways. Caveolin-1 (Cav-1), the principal coat protein of caveolae, has been associated with the regulation of signal transduction. Although Cav-1 can inhibit the expression of TGF-β in renal epithelial cells, the detailed molecular mechanisms of Cav-1 regulating TGF-β and EGF gene expression and TGF-β/ Smad3 (canonical) and non-Smad3 (non-canonical) like EGF/-ERK signaling are still unclear. The aim of this study is to explore the regulatory role of Cav-1 in the crosstalk between TGF-β and EGF. Stable Cav-1 overexpression or knockdown in Madin-Darby Canine Kidney (MDCK) cells was established for this study. In addition, various Cav-1 mutants (Y14D, Y14F and CSDmut) were also overexpressed in MDCK cells to investigate whether the phosphorylated tyrosine 14 residue or the Cav-1 scaffolding domain (CSD) is involved in the regulation of TGF-β or EGF signaling. Y14D and Y14F were generated by mimicking a phosphorylated and non-phosphorylated amino acid tyrosine 14, respectively. Another CSD mutant (F92A, T95A) was generated to inactivate the signal relay of CSD. Confocal imaging of Smad3 and ERK2 nuclear translocation and Western blotting of Smad3 and ERK2 phosphorylation were used to evaluate the activation of TGF-β and EGF signaling. Regarding the effects of Cav-1 on TGF-β1 and EGF signaling after TGF-β and EGF treatment, we found that the overexpression of wild-type Cav-1 inhibited Smad3 and ERK2 activation and nuclear translocation, whereas Cav-1 knockdown increased Smad3 and ERK2 activation and nuclear translocation. Due to crosstalk between TGF-β with EGF, overexpression of wild-type Cav-1 inhibited ERK2 activation and nuclear translocation by TGF-β treatment. In contrast, the overexpression of wild-type Cav-1 promoted Smad3 activation and nuclear translocation after EGF treatment. In addition, we confirmed this result by treating the cells with MβCD and CSD-peptide to affect Cav-1 function and compete with endogenous CSD. Furthermore, the Cav-1 mutants Y14D and CSDmut but not Y14F inhibited Smad3 activation and nuclear translocation. Therefore, we infer that Cav-1 has an inhibitory role and that the phosphorylated tyrosine 14 of Cav-1 plays an important role in inhibiting TGF-β and EGF signaling.

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