Elucidation of physiological function and mechanism of DA-Raf in cardiac hypertrophy and heart failure

我们已经鉴定出DA-Raf(缺失的A-Raf)，它是由Araf基因选择性剪接而产生的。它含有RAS结合域，但缺少激活域。为了阐明DA-Raf的生理功能及其机制，我们建立了DAraf基因缺陷(KO)小鼠，其中Araf的表达不受影响。KO组小鼠肺泡发育不良，原因是缺乏肌成纤维细胞。另一方面，高水平表达DA-Raf的肺泡上皮2型细胞(AEC2)可通过上皮-间充质转化为肌成纤维细胞。这些结果表明，DA-Raf通过调节AEC2-肌原纤维母细胞转化过程中的Ras-ERK通路，在肺泡化过程中发挥重要作用。

We have identified DA-Raf (deleted A-Raf), which is generated by alternative splicing from Araf gene. It contains the Ras-binding domain, but lacks the kinase domain. To elucidate physiological functions of DA-Raf and their mechanisms, we generated DAraf gene-deficient (KO) mice, in which Araf expression is not affected. Lung alveoli were poorly developed due to the lack of myofibroblasts in the KO mice. On the other hand, alveolar epithelial type 2 cells (AEC2), which expressed DA-Raf at high level, might transform by epithelial-mesenchymal transition to myofibroblasts. These results imply that DA-Raf plays essential roles in alveolarization by regulating the Ras-ERK pathway in AEC2-myofibrblast transition.