Cell Stress and Survival Group, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Institute, Copenhagen, Denmark.
Department of Biology, University of Rome Tor Vergata, Rome, Italy.
Cell Mol Life Sci. 2023 Aug 16;80(9):251. doi: 10.1007/s00018-023-04878-6.
AMBRA1 is a crucial factor for nervous system development, and its function has been mainly associated with autophagy. It has been also linked to cell proliferation control, through its ability to regulate c-Myc and D-type cyclins protein levels, thus regulating G1-S transition. However, it remains still unknown whether AMBRA1 is differentially regulated during the cell cycle, and if this pro-autophagy protein exerts a direct role in controlling mitosis too. Here we show that AMBRA1 is phosphorylated during mitosis on multiple sites by CDK1 and PLK1, two mitotic kinases. Moreover, we demonstrate that AMBRA1 phosphorylation at mitosis is required for a proper spindle function and orientation, driven by NUMA1 protein. Indeed, we show that the localization and/or dynamics of NUMA1 are strictly dependent on AMBRA1 presence, phosphorylation and binding ability. Since spindle orientation is critical for tissue morphogenesis and differentiation, our findings could account for an additional role of AMBRA1 in development and cancer ontogenesis.
AMBRA1 是神经系统发育的关键因素，其功能主要与自噬有关。它还通过调节 c-Myc 和 D 型细胞周期蛋白的蛋白水平来参与细胞增殖的控制，从而调节 G1-S 期转换。然而，AMBRA1 是否在细胞周期中差异调控，以及这种促自噬蛋白是否在控制有丝分裂中也发挥直接作用，目前仍不清楚。在这里，我们发现 CDK1 和 PLK1 这两种有丝分裂激酶可在有丝分裂过程中使 AMBRA1 上的多个位点发生磷酸化。此外，我们证明 AMBRA1 在有丝分裂时的磷酸化对于由 NUMA1 蛋白驱动的纺锤体功能和取向的正常化是必需的。事实上，我们发现 NUMA1 的定位和/或动力学严格依赖于 AMBRA1 的存在、磷酸化和结合能力。由于纺锤体取向对于组织形态发生和分化至关重要，我们的发现可以解释 AMBRA1 在发育和癌症发生中的额外作用。
