Disabled-2 (Dab2) is required for transforming growth factor beta-induced epithelial to mesenchymal transition (EMT)

作者：Prunier C; Howe PH^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280(17): 17540-17548.

DOI：10.1074/jbc.M500974200

Transforming growth factor beta (TGF beta) induces an epithelial to mesenchymal transition (EMT) during both physiological and pathological processes; however, the mechanism underlying this transition is not fully elucidated. Here, we have demonstrated that TGF beta induces the expression of the adaptor molecule disabled-2 (Dab2) concomitant with the promotion of EMT. We show that TGF beta induces a transient accumulation of Dab2 to the membrane and increases Dab2 binding to beta 1 integrin. Furthermore, small interfering RNA ( siRNA)mediated silencing of Dab2 expression in mouse mammary gland epithelial cells results in inhibition of integrin activation, shown by a decrease of both TGF beta-induced focal adhesion kinase phosphorylation and cellular adherence, leading to apoptosis and inhibition of EMT. Forced re-expression of human Dab2, not targeted by the mouse siRNA sequence, rescues cells from apoptosis and restores TGF beta-mediated integrin activation and EMT. These results are confirmed in the F9 teratocarcinoma cell line, a model for retinoic acid-induced visceral endoderm differentiation in which we demonstrate that ablation of retinoic acid-induced Dab2 expression levels, by stable siRNA silencing of Dab2, blocks visceral endoderm differentiation. Our findings indicate that Dab2 plays an important regulatory role during cellular differentiation and that induction of differentiation in the absence of Dab2 expression commits the cell to apoptosis.

• 出版日期2005-4-29