The molecular motor dynein is essential for mitotic spindle orientation, which defines the axis of cell division. The light intermediate chain subunits, LIC1 and LIC2, define biochemically and functionally distinct vertebrate dynein complexes, with LIC2-dynein playing a crucial role in ensuring spindle orientation. We reveal a novel, mitosis-specific interaction of LIC2-dynein with the cortical actin-bundling protein transgelin-2. Transgelin-2 is required for maintaining proper spindle length, equatorial metaphase chromosome alignment, spindle orientation and timely anaphase onset. We show that transgelin-2 stabilizes the cortical recruitment of LGN-NuMA, which together with dynein is required for spindle orientation. The opposing actions of transgelin-2 and LIC2-dynein maintain optimal cortical levels of LGN-NuMA. In addition, we show that the highly conserved serine 194 phosphorylation of LIC2 is required for proper spindle orientation, by maintaining mitotic centrosome integrity to ensure optimal astral microtubule nucleation. The work reveals two specific mechanisms through which LIC2-dynein regulates mitotic spindle orientation; namely, through a new interactor transgelin-2, which is required for engagement of LGN-NuMA with the actin cortex, and through mitotic phosphoregulation of LIC2 to control microtubule nucleation from the poles.

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分子运动动力蛋白对于有丝分裂纺锤体方向至关重要，它定义了细胞分裂的轴。轻中间链亚基 LIC1 和 LIC2 定义了生物化学和功能上不同的脊椎动物动力蛋白复合物，其中 LIC2-动力蛋白在确保纺锤体定向方面发挥着至关重要的作用。我们揭示了 LIC2-dynein 与皮质肌动蛋白捆绑蛋白 transgelin-2 的一种新颖的、有丝分裂特异性的相互作用。Transgelin-2 是维持适当的纺锤体长度、赤道中期染色体排列、纺锤体方向和及时的后期开始所必需的。我们发现 transgelin-2 可以稳定 LGN-NuMA 的皮质募集，LGN-NuMA 与动力蛋白一起是纺锤体定向所必需的。transgelin-2 和 LIC2-dynein 的相反作用维持 LGN-NuMA 的最佳皮质水平。此外，我们还表明，LIC2 的高度保守的丝氨酸 194 磷酸化对于正确的纺锤体方向是必需的，通过维持有丝分裂中心体的完整性来确保最佳的星体微管成核。这项工作揭示了 LIC2-动力蛋白调节有丝分裂纺锤体方向的两种具体机制；即，通过新的相互作用蛋白 transgelin-2（LGN-NuMA 与肌动蛋白皮层接合所需），并通过 LIC2 的有丝分裂磷酸调节来控制微管从两极成核。

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