果蝇体内调控细胞命运的重要蛋白质Miranda的调控过程，并不像科学家想象中那么复杂。美国俄勒冈大学（University of Oregon）研究人员发现有一种非典型蛋白激酶C（aPKC）参与并独立决定子代细胞的分化方向。生化学家Kenneth Prehoda表示，在干细胞分裂时，其含有aPKC 的一侧或皮质区域仍以干细胞形式存在，而含有Miranda 的其他区域则分化为其他类型的细胞，如组成中枢神经系统的神经细胞。相关机制发表在5月12日出版的Current Biology杂志上。
论文指出，与众多科学人员理论推测的不同，干细胞分裂并非复杂的蛋白失活级联过程，而是一种被称为ATP的高能核苷在aPKC的催化下脱去一分子磷酸，脱去的磷酸分子继而又在aPKC的催化下与Miranda结合。这个过程使Miranda与aPKC脱离，并决定子细胞的分化方向。Prehoda 从生化角度上进行解释认为，Miranda在aPKC作用下磷酸化，转化为失活底物，并将其推向细胞的其他区域。
这篇文章的大部分内容着眼于一些复杂理论的不确切之处。Prehoda指出，对于干细胞的分裂机制存在许多观点，但大多数理论很复杂且难以解释。新的发现给出一个更简单的机制，而且许多其他类型细胞的分裂机制也可能与此类似。研究人员表示，极性如何产生是一个基本的研究问题。只有了解极性产生的机制，才能找到合理的方法用于干细胞的特定治疗。(生物谷Bioon.com)
生物谷推荐原始出处：
Current Biology, 16 April 2009 doi:10.1016/j.cub.2009.03.056
aPKC Phosphorylates Miranda to Polarize Fate Determinants during Neuroblast Asymmetric Cell Division
Scott X. Atwood1andKenneth E. Prehoda1,,
1 Institute of Molecular Biology and Department of Chemistry, University of Oregon, Eugene, OR 97403, USA
Summary
Asymmetric cell divisions generate daughter cells with distinct fates by polarizing fate determinants into separate cortical domains. Atypical protein kinase C (aPKC) is an evolutionarily conserved regulator of cell polarity. In Drosophila neuroblasts, apically restricted aPKC is required for segregation of neuronal differentiation factors such as Numb and Miranda to the basal cortical domain. Whereas Numb is polarized by direct aPKC phosphorylation, Miranda asymmetry is thought to occur via a complicated cascade of repressive interactions (aPKC | Lgl | myosin II | Miranda).Here we provide biochemical, cellular, and genetic data showing that aPKC directly phosphorylates Miranda to exclude it from the cortex and that Lgl antagonizes this activity. Miranda is phosphorylated by aPKC at several sites in its cortical localization domain and phosphorylation is necessary and sufficient for cortical displacement, suggesting that the repressive-cascade model is incorrect. In investigating key results that led to this model, we found that Y-27632, a Rho kinase inhibitor used to implicate myosin II, efficiently inhibits aPKC. Lgl3A, a nonphosphorylatable Lgl variant used to implicate Lgl in this process, inhibits the formation of apical aPKC crescents in neuroblasts. Furthermore, Lgl directly inhibits aPKC kinase activity.Miranda polarization during neuroblast asymmetric cell division occurs by displacement from the apical cortex by direct aPKC phosphorylation. Rather than mediating Miranda cortical displacement, Lgl instead promotes aPKC asymmetry by regulating its activity. The role of myosin II in neuroblast polarization, if any, is unknown.
