Sini Patrizia, Cannas Angela, Koleske Anthony J, Di Fiore Pier Paolo, Scita Giorgio
Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy.
Nat Cell Biol. 2004 Mar;6(3):268-74. doi: 10.1038/ncb1096. Epub 2004 Feb 22.
The non-receptor tyrosine kinase Abl participates in receptor tyrosine kinase (RTK)-induced actin cytoskeleton remodelling, a signalling pathway in which the function of Rac is pivotal. More importantly, the activity of Rac is indispensable for the leukaemogenic ability of the BCR-Abl oncoprotein. Thus, Rac might function downstream of Abl and be activated by it. Here, we elucidate the molecular mechanisms through which Abl signals to Rac in RTK-activated pathways. We show that Sos-1, a dual guanine nucleotide-exchange factor (GEF), is phosphorylated on tyrosine, after activation of RTKs, in an Abl-dependent manner. Sos-1 and Abl interact in vivo, and Abl-induced tyrosine phosphorylation of Sos-1 is sufficient to elicit its Rac-GEF activity in vitro. Genetic or pharmacological interference with Abl (and the related kinase Arg) resulted in a marked decrease in Rac activation induced by physiological doses of growth factors. Thus, our data identify the molecular connections of a pathway RTKs-Abl-Sos-1-Rac that is involved in signal transduction and actin remodelling.
非受体酪氨酸激酶Abl参与受体酪氨酸激酶（RTK）诱导的肌动蛋白细胞骨架重塑，在该信号通路中Rac的功能至关重要。更重要的是，Rac的活性对于BCR-Abl癌蛋白的致白血病能力不可或缺。因此，Rac可能在Abl下游发挥作用并被其激活。在此，我们阐明了在RTK激活的信号通路中Abl向Rac发出信号的分子机制。我们发现，双鸟嘌呤核苷酸交换因子（GEF）Sos-1在RTK激活后以Abl依赖的方式发生酪氨酸磷酸化。Sos-1与Abl在体内相互作用，并且Abl诱导的Sos-1酪氨酸磷酸化足以在体外引发其Rac-GEF活性。对Abl（以及相关激酶Arg）进行基因或药理学干扰会导致生理剂量的生长因子诱导的Rac激活显著降低。因此，我们的数据确定了RTKs-Abl-Sos-1-Rac信号通路在信号转导和肌动蛋白重塑中的分子联系。
