Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation

Caveolin-1 (Cav1) is an essential component of caveolae whose Src kinase-dependent phosphorylation on tyrosine 14 (Y14) is associated with regulation of focal adhesion dynamics. However, the relationship between these disparate functions remains to be elucidated. Caveola biogenesis requires expression of both Cav1 and cavin-1, but Cav1Y14 phosphorylation is dispensable. In this paper, we show that Cav1 tyrosine phosphorylation induces caveola biogenesis via actin-dependent mechanotransduction and inactivation of the Egr1 (early growth response-1) transcription factor, relieving inhibition of endogenousCav1andcavin-1genes. Cav1 phosphorylation reduces Egr1 binding to Cav1 and cavin-1 promoters and stimulates their activity. In MDA-231 breast carcinoma cells that express elevated levels of Cav1 and caveolae, Egr1 regulated Cav1, and cavin-1 promoter activity was dependent on actin, Cav1, Src, and Rho-associated kinase as well as downstream protein kinase C (PKC) signaling. pCav1 is therefore a mechanotransducer that acts via PKC to relieve Egr1 transcriptional inhibition of Cav1 and cavin-1, defining a novel feedback regulatory loop to regulate caveola biogenesis.

小窝蛋白1（Caveolin-1, Cav1）是细胞质膜微囊（caveolae）的必需组成成分，其酪氨酸14位点（Y14）上依赖Src激酶的磷酸化与黏着斑动力学的调控密切相关。然而，这两类截然不同的功能之间的关联仍有待阐明。细胞质膜微囊的生物发生需要Cav1与cavin-1共同表达，但Cav1 Y14的磷酸化并非必需。本研究发现，Cav1的酪氨酸磷酸化可通过肌动蛋白依赖的机械转导通路，以及早期生长反应因子1（Egr1, early growth response-1）转录因子的失活，解除对内源性Cav1与cavin-1基因的抑制，从而诱导细胞质膜微囊的生物发生。Cav1磷酸化会降低Egr1与Cav1及cavin-1启动子的结合能力，并激活二者的转录活性。在高表达Cav1与细胞质膜微囊的MDA-231乳腺癌细胞中，Egr1对Cav1及cavin-1启动子活性的调控依赖于肌动蛋白、Cav1、Src以及Rho相关激酶，同时也依赖下游的蛋白激酶C（PKC, protein kinase C）信号通路。因此，磷酸化Cav1（pCav1）是一种通过PKC信号通路解除Egr1对Cav1和cavin-1转录抑制的机械转导分子，由此确立了一条调控细胞质膜微囊生物发生的新型反馈调控环路。