Src inhibitors, PP2 and dasatinib, increase retinoic acid-induced association of Lyn and c-Raf (S259) and enhance MAPK-dependent differentiation of myeloid leukemia cells.
Src inhibitors, PP2 and dasatinib, increase retinoic acid-induced association of Lyn and c-Raf (S259) and enhance MAPK-dependent differentiation of myeloid leukemia cells.
复制标题
作者：
全反式维甲酸（ATRA）诱导的人髓系白血病细胞分化以持续的MAPK信号传导为特征。零碎的数据表明，Src家族激酶（SFK）抑制剂可增强分化，因此具有潜在的治疗价值。目前的研究表明，SFK抑制剂PP2和达沙替尼增强了MAPK信号传导的各个方面，并调节了包括CD11b和p47phox在内的一系列分化标志物。HL-60和NB4髓系白血病细胞在抑制剂联合治疗下表现出atra诱导的G1/0阻滞/分化加速。我们还鉴定了由抑制剂增强的含有Lyn和c- raf的MAPK信号复合物的组分。PP2和达沙替尼增加atra诱导的Lyn和c-Raf （total和c-RafpS259）的表达及其相互作用。lynn相关丝氨酸/苏氨酸激酶CK2也与c-Raf和c-RafpS259络合，KSR1支架蛋白结合c-Raf、Lyn和ERK。抑制剂增加了c-Raf/ERK的关联，这是重要的，因为ERK可能在假定的反馈机制中引起c-Raf c-末端结构域（CTD）磷酸化。与此一致，抑制剂治疗引起更多的CTD磷酸化。Lyn敲除降低c-Raf CTD和S259磷酸化。这是第一个表明SFK抑制剂通过一个可能的反馈回路增强atra诱导的分化的证据，该反馈回路涉及ksr1支架的c-Raf和ERK与Lyn和CK2络合。
All-trans-retinoic-acid (ATRA)-induced differentiation of human myeloid leukemia cells is characterized by persistent MAPK signaling. Fragmentary data suggests Src family kinase (SFK) inhibitors enhance differentiation and thus have potential therapeutic value. The present study shows that SFK inhibitors PP2 and dasatinib enhance aspects of MAPK signaling and regulate a panel of differentiation markers including CD11b and p47phox. HL-60 and NB4 myeloid leukemia cells show accelerated ATRA-induced G1/0 arrest/differentiation with inhibitor co-treatment. We also identified components of a Lyn- and c-Raf-containing MAPK signaling complex augmented by the inhibitors. PP2 and dasatinib increased ATRA-induced expression of Lyn and c-Raf (total and c-RafpS259) and their interaction. The Lyn-associated serine/threonine kinase CK2 also complexed with c-Raf and c-RafpS259, and the KSR1 scaffold protein bound c-Raf, Lyn, and ERK. c-Raf/ERK association was increased by the inhibitors, which is significant since ERK may cause c-Raf C-terminal domain (CTD) phosphorylation in a putative feedback mechanism. Consistent with this, inhibitor treatment caused more CTD phosphorylation. Lyn knockdown decreased c-Raf CTD and S259 phosphorylation. This is the first evidence suggesting SFK inhibitors enhance ATRA-induced differentiation through a possible feedback loop involving KSR1-scaffolded c-Raf and ERK complexed with Lyn and CK2.
登录
查看更多内容
影响因子：
4.8
作者：
Hong, Seung-Keun;Yoon, Seunghee;Park, Jong-In
通讯作者：
Park, Jong-In
影响因子：
3.6
作者：
Kim, M. P.;Park, S. I.;Kopetz, S.;Gallick, G. E.
通讯作者：
Gallick, G. E.
影响因子：
5.7
作者：
Miranda, Michelle B.;Redner, Robert L.;Johnson, Daniel E.
通讯作者：
Johnson, Daniel E.
影响因子：
20.3
作者：
Dos Santos, Ceric;Demur, Ceile;Recher, Christian
通讯作者：
Recher, Christian
影响因子：
11.4
作者：
Okamoto, M.;Hayakawa, F.;Naoe, T.
通讯作者：
Naoe, T.