Institute for Regenerative Cures, University of California, Davis, CA, USA; Department of Dermatology, University of California, Davis, CA, USA; Department of Ophthalmology, University of California, Davis, CA, USA; Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Trauma Center of Postgraduate Medical School, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, P.R. China.
Key Laboratory of Systems and Control, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, No. 55 Zhongguancun East Road, Beijing 100190, P.R. China.
Biomaterials. 2018 Jul;170:82-94. doi: 10.1016/j.biomaterials.2018.03.052. Epub 2018 Apr 3.
Orientation of cell division plane plays a crucial role in morphogenesis and regeneration. Misoriented cell division underlies many important diseases, such as cancer. Studies with Drosophila and C. elegance models show that Src, a proto-oncogene tyrosine-protein kinase, is a critical regulator of this aspect of mitosis. However, the role for Src in controlling cell division orientation in mammalian cells is not well understood. Using genetic and pharmacological approaches and two extracellular signals to orient cell division, we demonstrated a critical role for Src. Either knockout or pharmacological inhibition of Src would retain the fidelity of cell division orientation with the long-axis orientation of mother cells. Conversely, re-expression of Src would decouple cell division orientation from the pre-division orientation of the long axis of mother cells. Cell division orientation in human breast and gastric cancer tissues showed that the Src activation level correlated with the degree of mitotic spindle misorientation relative to the apical surface. Examination of proteins associated with cortical actin revealed that Src activation regulated the accumulation and local density of adhesion proteins on the sites of cell-matrix attachment. By analyzing division patterns in the cells with or without Src activation and through use of a mathematical model, we further support our findings and provide evidence for a previously unknown role for Src in regulating cell division orientation in relation to the pre-division geometry of mother cells, which may contribute to the misoriented cell division.
细胞分裂平面的取向在形态发生和再生中起着至关重要的作用。错位的细胞分裂是许多重要疾病的基础，如癌症。使用果蝇和 C. elegans 模型的研究表明，Src，一种原癌基因酪氨酸蛋白激酶，是有丝分裂这一方面的关键调节因子。然而，Src 在控制哺乳动物细胞中细胞分裂方向的作用尚不清楚。我们使用遗传和药理学方法以及两种细胞外信号来定向细胞分裂，证明了 Src 的关键作用。Src 的敲除或药理学抑制会保持细胞分裂方向与母细胞长轴方向的保真度。相反，Src 的重新表达会使细胞分裂方向与母细胞长轴的分裂前方向脱钩。人乳腺癌和胃癌组织中的细胞分裂方向表明，Src 的激活水平与有丝分裂纺锤体相对于顶端表面的错位程度相关。对与皮质肌动蛋白相关的蛋白的检测表明，Src 的激活调节了粘附蛋白在细胞-基质附着部位的积累和局部密度。通过分析具有或不具有 Src 激活的细胞中的分裂模式，并通过使用数学模型，我们进一步支持我们的发现，并提供证据表明 Src 在调节细胞分裂方向方面具有以前未知的作用，与母细胞的分裂前几何形状有关，这可能导致细胞分裂错位。
