Langton Paul F, Colombani Julien, Aerne Birgit L, Tapon Nicolas
Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Dev Cell. 2007 Dec;13(6):773-82. doi: 10.1016/j.devcel.2007.11.005.
Src-family kinases (SFKs) control a variety of biological processes, from cell proliferation and differentiation to cytoskeletal rearrangements. Abnormal activation of SFKs has been implicated in a wide variety of cancers and is associated with metastatic behavior (Yeatman, 2004). SFKs are maintained in an inactive state by inhibitory phosphorylation of their C-terminal region by C-terminal Src kinase (Csk). We have identified Drosophila Ankyrin-repeat, SH3-domain, and Proline-rich-region containing Protein (dASPP) as a regulator of Drosophila Csk (dCsk) activity. dASPP is the homolog of the mammalian ASPP proteins, which are known to bind to and stimulate the proapoptotic function of p53. We show that dASPP is a positive regulator of dCsk. First, dASPP loss-of-function strongly enhances the specific phenotypes of dCsk mutants in wing epithelial cells. Second, dASPP interacts physically with dCsk to potentiate the inhibitory phosphorylation of Drosophila Src (dSrc). Our results suggest a role for dASPP in maintaining epithelial integrity through dCsk regulation.
Src家族激酶（SFKs）控制着从细胞增殖与分化到细胞骨架重排等多种生物学过程。SFKs的异常激活与多种癌症有关，并与转移行为相关（Yeatman，2004年）。通过C末端Src激酶（Csk）对其C末端区域进行抑制性磷酸化，SFKs维持在无活性状态。我们已鉴定出果蝇锚蛋白重复序列、SH3结构域和富含脯氨酸区域的蛋白（dASPP）作为果蝇Csk（dCsk）活性的调节因子。dASPP是哺乳动物ASPP蛋白的同源物，已知其可结合并刺激p53的促凋亡功能。我们表明dASPP是dCsk的正向调节因子。首先，dASPP功能丧失强烈增强了翅上皮细胞中dCsk突变体的特定表型。其次，dASPP与dCsk发生物理相互作用，以增强果蝇Src（dSrc）的抑制性磷酸化。我们的结果表明dASPP在通过dCsk调节维持上皮完整性中发挥作用。
