Schenck Annette, Goto-Silva Livia, Collinet Claudio, Rhinn Muriel, Giner Angelika, Habermann Bianca, Brand Michael, Zerial Marino
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Cell. 2008 May 2;133(3):486-97. doi: 10.1016/j.cell.2008.02.044.
During development of multicellular organisms, cells respond to extracellular cues through nonlinear signal transduction cascades whose principal components have been identified. Nevertheless, the molecular mechanisms underlying specificity of cellular responses remain poorly understood. Spatial distribution of signaling proteins may contribute to signaling specificity. Here, we tested this hypothesis by investigating the role of the Rab5 effector Appl1, an endosomal protein that interacts with transmembrane receptors and Akt. We show that in zebrafish, Appl1 regulates Akt activity and substrate specificity, controlling GSK-3beta but not TSC2. Consistent with this pattern, Appl1 is selectively required for cell survival, most critically in highly expressing tissues. Remarkably, Appl1 function requires its endosomal localization. Indeed, Akt and GSK-3beta, but not TSC2, dynamically associate with Appl1 endosomes upon growth factor stimulation. We propose that partitioning of Akt and selected effectors onto endosomal compartments represents a key mechanism contributing to the specificity of signal transduction in vertebrate development.
在多细胞生物的发育过程中，细胞通过非线性信号转导级联反应对细胞外信号作出反应，其主要成分已被确定。然而，细胞反应特异性背后的分子机制仍知之甚少。信号蛋白的空间分布可能有助于信号特异性。在这里，我们通过研究Rab5效应蛋白Appl1（一种与跨膜受体和Akt相互作用的内体蛋白）的作用来验证这一假设。我们发现，在斑马鱼中，Appl1调节Akt活性和底物特异性，控制GSK-3β但不控制TSC2。与这种模式一致，Appl1是细胞存活选择性所需的，在高表达组织中最为关键。值得注意的是，Appl1的功能需要其在内体中的定位。事实上，在生长因子刺激下，Akt和GSK-3β而非TSC2会动态地与Appl1内体结合。我们提出，将Akt和选定的效应蛋白分配到内体区室是脊椎动物发育中信号转导特异性的关键机制。
