在我們先前的研究中發現過度表達Ha-RasV12會造成YAP即使在高密度的狗的腎臟上皮細胞還是維持YAP入核表達，並且是透過跟hippo pathway無關的機制。此外，過度表達Ha-RasV12也會降低Cav1的表達以及細胞連結的完整性。Cav1 曾經被報導可以透過招募E-cadherin 和β-catenin 複合體來穩定細胞連結。Furukawa 等人的研究當中，也發現了破壞細胞連結的肌動蛋白張力，會造成YAP在高密度的上皮細胞中入核表達。因此，我們認為過度表達Ha-RasV12所造成的Cav1下降，會去破壞細胞連結，進而促進YAP在高密度的細胞當中入核表達。正常的MK4細胞有典型的上皮細胞型態，並有myosin IIB接在細胞骨架上形成完整的細胞連結。在IPTG 的作用下，過度表達Ha-RasV12造成細胞連結鬆散和myosin IIB異位，進而造成YAP的入核表達，然而在過度表達Cav1之後，則可以避免這些現象產生。在Cav1缺失的細胞當中，也可以發現細胞連結鬆散以及myosin IIB 異位，並且造成YAP入核的現象。用肌動蛋白張力抑制劑像是ML7 和Blebbistatin 來抑制肌動蛋白張力之後，也會降低myosin IIB 在細胞連結處的表達，以及促進YAP 入核。Cav1 被發現和調控ERK活性有關。我們也發現U0126 (MEK抑制劑)可以有效的抑制Ha-RasV12過度表達以及Cav1 缺失所誘導的YAP 入核表達。被正常細胞包圍的YAP 入核的細胞傾向於被擠出上方。Ha-RasV12 過度表達會造成細胞形成頂端的細胞堆疊。然而，使用Verteporfin 抑制YAP 的活性並沒有辦法抑制Ha-RasV12過度表達造成的細胞堆疊，且在細胞堆疊的區域，YAP 表達在細胞質當中。此外，EHT1864 (Rac inhibitor) 能有效的抑制Ha-RasV12過度表達所造成的細胞堆疊，但無法抑制YAP的入核表達。總結來說，這些結果顯示Cav1在穩定細胞連結的完整性當中扮演很重要的角色，進而調控YAP 的入核表達。然而，細胞堆疊的形成需要Rac的活性而非YAP入核。

Our previous study showed that Ha-RasV12 overexpression induced nuclear translocation of hippo effector Yes-associated protein (YAP) in MDCK cells via hippo-independent pathway even at confluent stage. Ha-RasV12 overexpression leads to downregulation of caveolin-1 (Cav1) and disruption of junction integrity. Cav1 was reported to recruit E-cadherin/β-catenin complex and stabilize cell junction. Furukawa et al. showed that disruption of actomyosin tension in cell junction caused YAP nuclear localization in epithelial cells under high density. We hypothesize that Ha-RasV12-decreased Cav1 leads to the lessened of actomyosin tension, which subsequently facilitates YAP nuclear localization. MK4 cells exhibits typical epithelial colonies with well-organized junctional actin belts lined with myosin IIB. Upon IPTG administration, Ha-RasV12 overexpression resulted in YAP nuclear translocation and loosened cell junction with disturbed distribution of myosin IIB, which is prevented by overexpression of Cav1. Cav1 knockdown showed loosened cell junction with disturbed distribution of myosin IIB and the augmentation of YAP nuclear localization. Treatment of actomyosin tension inhibitors, including ML7 (myosin light chain kinase inhibitor), blebbistatin (myosin II inhibitor), induced YAP nuclear translocation and disturbed distribution of myosin IIB in confluent MK4 cells. The regulation of ERK activation has been found related to Cav1. U0126 (MEK inhibitor) abolished Ha-RasV12 overexpression- and Cav1 absence-induced YAP nuclear translocation, suggesting that MEK signaling is required for Ha-RasV12-induced YAP nuclear translocation. Ha-RasV12 overexpressing cells exhibited apically cellular aggregates in overconfluent MK4 cells. Inhibition of YAP activity by verteporfin did not abolish Ha-RasV12-induced cellular aggregates. Immunostaining results showed that cells in aggregate area displayed cytosolic YAP, but not nuclear YAP. Although inhibition of Rac activity by EHT1864 inhibited Ha-RasV12-induced cellular aggregate, it did not change RasV12-induced YAP nuclear translocation. Taken together, these data suggest that Cav1 functions to stabilize cell junction integrity, which tends to retains YAP in the cytosol in confluent MDCK cells. Moreover, Rac activity, but not nuclear YAP, seems to be more important for multilayer cellular aggregates formation.

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