Crosstalk between BCR/ABL oncoprotein and CXCR4 signaling through a Src family kinase in human leukemia cells.
Crosstalk between BCR/ABL oncoprotein and CXCR4 signaling through a Src family kinase in human leukemia cells.
复制标题
DOI：
10.1084/jem.20020519
复制
发表时间：
2002-09-02
期刊：
影响因子：
--
通讯作者：
Gewirtz AM
中科院分区：
文献类型：
--
作者：
Ptasznik A;Urbanowska E;Chinta S;Costa MA;Katz BA;Stanislaus MA;Demir G;Linnekin D;Pan ZK;Gewirtz AM
基质衍生因子（SDF）-1及其G蛋白偶联受体CXCR 4调节干/祖细胞在骨髓中的迁移和保留，并且是造血所需的。我们在这里展示了正常祖细胞中CXCR 4和Src相关激酶林恩之间的相互作用。我们证明，CXCR 4依赖性刺激林恩与磷脂酰肌醇3-激酶（PI 3-激酶）的激活。这种涉及Src相关激酶和PI 3激酶的趋化因子信号传导似乎是BCR/ABL的靶点，BCR/ABL是一种仅在白血病细胞中表达的融合癌蛋白。我们发现磷酸化BCR/ABL与林恩的结合导致林恩和PI 3-激酶的组成性激活，沿着这些激酶对SDF-1刺激的反应性的完全丧失。用STI 571抑制BCR/ABL酪氨酸激酶恢复林恩对SDF-1信号传导的响应性。因此，BCR/ABL通过酪氨酸激酶依赖性机制干扰林恩功能。因此，阻断林恩酪氨酸激酶可抑制BCR/ABL依赖性和CXCR 4依赖性细胞运动。我们的研究结果首次表明，在白血病细胞中，BCR/ABL和CXCR 4通路之间存在Lyn-mediated病理性串扰，这破坏了趋化因子信号传导和趋化性，并增加了未成熟细胞从骨髓中逃逸的能力。这些结果定义了一个Src酪氨酸激酶依赖的机制，BCR/ABL（和潜在的其他癌蛋白）失调G蛋白偶联受体信号和功能的哺乳动物前体。
Stromal-derived factor (SDF)-1 and its G protein–coupled receptor, CXCR4, regulate stem/progenitor cell migration and retention in the marrow and are required for hematopoiesis. We show here an interaction between CXCR4 and the Src-related kinase, Lyn, in normal progenitors. We demonstrate that CXCR4-dependent stimulation of Lyn is associated with the activation of phosphatidylinositol 3-kinase (PI3-kinase). This chemokine signaling, which involves a Src-related kinase and PI3-kinase, appears to be a target for BCR/ABL, a fusion oncoprotein expressed only in leukemia cells. We show that the binding of phosphorylated BCR/ABL to Lyn results in the constitutive activation of Lyn and PI3-kinase, along with a total loss of responsiveness of these kinases to SDF-1 stimulation. Inhibition of BCR/ABL tyrosine kinase with STI571 restores Lyn responsiveness to SDF-1 signaling. Thus, BCR/ABL perturbs Lyn function through a tyrosine kinase-dependent mechanism. Accordingly, the blockade of Lyn tyrosine kinase inhibits both BCR/ABL-dependent and CXCR4-dependent cell movements. Our results demonstrate, for the first time, that Lyn-mediated pathological crosstalk exists between BCR/ABL and the CXCR4 pathway in leukemia cells, which disrupts chemokine signaling and chemotaxis, and increases the ability of immature cells to escape from the marrow. These results define a Src tyrosine kinases-dependent mechanism whereby BCR/ABL (and potentially other oncoproteins) dysregulates G protein–coupled receptor signaling and function of mammalian precursors.
登录
查看更多内容
影响因子：
20.3
作者：
Kim, CH;Broxmeyer, HE
通讯作者：
Broxmeyer, HE
影响因子：
64.5
作者：
GROFFEN, J;STEPHENSON, JR;GROSVELD, G
通讯作者：
GROSVELD, G
影响因子：
4.8
作者：
Cao, WH;Luttrell, LM;Collins, S
通讯作者：
Collins, S
影响因子：
4.8
作者：
Daulhac, L;Kowalski-Chauvel, A;Seva, C
通讯作者：
Seva, C
影响因子：
11.4
作者：
Daub, H;Wallasch, C;Ullrich, A
通讯作者：
Ullrich, A