Mizuchi Daisuke, Kurosu Tetsuya, Kida Aiko, Jin Zhen-Hua, Jin Aishun, Arai Ayako, Miura Osamu
Department of Hematology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Biochem Biophys Res Commun. 2005 Jan 21;326(3):645-51. doi: 10.1016/j.bbrc.2004.11.086.
The BCR/ABL fusion tyrosine kinase activates various intracellular signaling pathways, thus causing chronic myeloid leukemia (CML). Here we demonstrate that the inducible expression of BCR/ABL in a murine hematopoietic cell line, TonB210, leads to the activation of the Ras family small GTPase Rap1, which is inhibited by the ABL kinase inhibitor imatinib. The Rap1 activity in a CML cell line, K562, was also inhibited by imatinib. Inhibition of Rap1 activation by a dominant negative mutant of Rap1, Rap1-N17, or SPA-1 inhibited the BCR/ABL-induced activation of Elk-1. BCR/ABL also activated in a kinase activity-dependent manner the B-Raf kinase, which is an effector molecule of Rap1 and a potent activator of the MEK/Erk/Elk-1 signaling pathway. Together, these data suggest that, in addition to the well-established Ras/Raf-1 pathway, BCR/ABL activates the alternative signaling pathway involving Rap1 and B-Raf to activate Erk, which may play important roles in leukemogenesis.
BCR/ABL融合酪氨酸激酶激活多种细胞内信号通路，从而引发慢性髓性白血病（CML）。在此我们证明，在小鼠造血细胞系TonB210中诱导表达BCR/ABL会导致Ras家族小GTP酶Rap1激活，而该激活被ABL激酶抑制剂伊马替尼所抑制。在CML细胞系K562中的Rap1活性也被伊马替尼抑制。通过Rap1的显性负性突变体Rap1-N17或SPA-1抑制Rap1激活，会抑制BCR/ABL诱导的Elk-1激活。BCR/ABL还以激酶活性依赖的方式激活B-Raf激酶，B-Raf激酶是Rap1的效应分子以及MEK/Erk/Elk-1信号通路的强效激活剂。总之，这些数据表明，除了已确立的Ras/Raf-1通路外，BCR/ABL还激活涉及Rap1和B-Raf的替代信号通路来激活Erk，这可能在白血病发生中起重要作用。
