Src activation decouples cell division orientation from cell geometry in mammalian cells

Abstract

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.

TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling

“…Changes in TPX2 expression, either down or upregulation, lead to mitotic aberrations that prevent proper chromosome segregation, leading to CIN [ 27 , 28 ]. On the other hand, although SFKs allow progression through the early phases of the cell cycle [ 23 ] and dasatinib efficiently arrests the cell cycle in G 0 /G 1 [ 83 , 84 , 85 , 86 ], in recent years there is strong evidence that SFKs are also functional during mitosis [ 67 , 87 , 88 , 89 , 90 , 91 ].…”

TPX2 expression promotes sensitivity to dasatinib in breast cancer by activating the YAP transcriptional signaling

“…Changes in TPX2 expression, either down or upregulation, lead to mitotic aberrations that prevent proper chromosome segregation, leading to CIN [26,27]. On the other hand, although SFKs allow progression through the early phases of the cell cycle [23] and dasatinib efficiently arrests the cell cycle in G0/G1 [83][84][85][86], in recent years there is strong evidence that SFKs are also functional during mitosis [67,[87][88][89][90][91].…”