Src family tyrosine kinases are activated by Flt3 and are involved in the proliferative effects of leukemia-associated Flt3 mutations
Src family tyrosine kinases are activated by Flt3 and are involved in the proliferative effects of leukemia-associated Flt3 mutations
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DOI：
10.1016/j.exphem.2005.01.004
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发表时间：
2005-04-01
影响因子：
2.6
通讯作者：
Corey, SJ
中科院分区：
文献类型：
--
作者：
Robinson, LJ;Xue, J;Corey, SJ
Objective.造血生长因子受体Fms样酪氨酸激酶-3（FIB）调节骨髓和B细胞前体的存活和增殖。Flt 3的激活突变是急性髓性白血病（AML）中最常见的分子异常，并且在白血病发生中具有明显的作用。然而，信号通路介导Flt 3的影响是不完全理解。Src激酶的作用是未知的，虽然有些，如林恩，也被链接到白血病。本研究探讨Src激酶在Flt 3信号转导中的作用以及白血病相关Flt 3突变的致癌作用。我们研究了Src激酶在表达野生型Flt 3或组成型活性突变体的人白血病骨髓细胞系中的激活和功能作用，以及在稳定转导人野生型或突变体Flt 3的细胞中的作用。野生型FIB的Flt 3配体刺激增加Src激酶林恩的磷酸化。组成型林恩磷酸化和激活被发现在细胞表达组成型活性Flt 3突变体。Src激酶参与密切相关受体的下调，但Sre抑制剂对配体刺激的Flt 3降解或Flt 3突变体的快速降解没有影响。然而，突变Flt 3表达导致的生长因子非依赖性增殖确实依赖于Src激酶的活性。我们的研究首次揭示了Sre激酶参与Flt 3信号传导，通过组成型活性Flt 3突变体以及配体刺激的野生型受体激活林恩，并表明Src激酶抑制剂阻断AML中发现的Flt 3突变体的增殖作用。因此，Src激酶可能是F10相关AML抑制剂治疗的靶点。(c)2005年国际实验血液学学会。爱思唯尔公司出版
Objective. The hematopoietic growth factor receptor, Fms-like tyrosine kinase-3 (FIB), modulates survival and proliferation of myeloid and B-cell precursors. Activating mutations of Flt3 are the most common molecular abnormalities in acute myeloid leukemia (AML) and have an apparent role in leukernogenesis. However, signaling pathways mediating Flt3 effects are incompletely understood. The role of Src kinases is unknown, although some, such as Lyn, have also been linked to leukemogenesis. This study examines the role of Src kinases in Flt3 signaling and the oncogenic effects of leukemia-associated Flt3 mutations.Materials and Methods. We examined the activation and functional roles of Src kinases in human leukemic myeloid cell lines expressing wild-type Flt3 or a constitutively active mutant, and in cells stably transduced with human wild-type or mutant Flt3.Results. Flt3 ligand stimulation of wild-type FIB increased phosphorylation of Src kinase Lyn. Constitutive Lyn phosphorylation and activation was found in cells expressing constitutively active Flt3 mutants. Src kinases are implicated in downregulation of closely related receptors, but Sre inhibitors had no effect on ligand-stimulated Flt3 degradation, or on the rapid degradation of an Flt3 mutant. However, growth-factor-independent proliferation resulting from mutant Flt3 expression did depend on the activity of Src kinases.Conclusion. Our studies reveal for the first time the involvement of Sre kinases in Flt3 signaling, with activation of Lyn by constitutively active Flt3 mutants as well as ligand-stimulated wildtype receptor, and show that Src kinase inhibitors block proliferative effects of Flt3 mutants found in AML. Thus, Src kinases may represent targets for inhibitor therapy in F10-related AML. (c) 2005 International Society for Experimental Hematology. Published by Elsevier Inc.