Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells
Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells
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DOI：
10.1182/blood-2007-11-121681
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发表时间：
2008-08-01
期刊：
影响因子：
20.3
通讯作者：
Lackmann, Martin
中科院分区：
文献类型：
--
作者：
Wimmer-Kleikamp, Sabine H.;Nievergall, Eva;Lackmann, Martin
Eph受体和细胞表面ephrin配体的信号调节粘附细胞的特性，从而协调细胞的运动和定位在正常和致癌的发展。虽然细胞接触依赖性Eph激活经常导致细胞-细胞排斥，但也可能导致完全相反的反应，细胞-细胞粘附。然而，调节这些不同功能的分子原理仍然存在争议。我们通过分析EphA 3阳性LK 63前B急性淋巴细胞白血病细胞的ephrin-A5诱导的细胞形态学变化，研究了这种转换的细胞生物学机制。它们暴露于肝配蛋白-A5表面导致从悬浮/非极化到粘附/极化细胞类型的快速转化，这是一种依赖于EphA 3功能在没有Eph激酶信号传导的情况下操作的转变。内源性蛋白酪氨酸磷酸酶（PTP）活性有效地减弱了LK 63细胞的细胞形态变化和粘附，由此PTP抑制和生产性EphA 3-磷酸酪氨酸信号传导将表型逆转为具有浓缩细胞骨架的非粘附细胞。我们的研究结果表明，Eph相关的PTP活动不仅控制受体的磷酸化水平，但作为一个结果开关的反应ephrin接触排斥粘附，这可能在造血系统肿瘤的病理中发挥作用。
Signaling by Eph receptors and cellsurface ephrin ligands modulates adhesive cell properties and thereby coordinates cell movement and positioning in normal and oncogenic development. While cell contact-dependent Eph activation frequently leads to cell-cell repulsion, also the diametrically opposite response, cell-cell adhesion, is a probable outcome. However, the molecular principles regulating such disparate functions have remained controversial. We have examined cell-biologic mechanisms underlying this switch by analyzing ephrin-A5-induced cell-morphologic changes of EphA3-positive LK63 pre-B acute lymphoblastic leukemia cells. Their exposure to ephrin-A5 surfaces leads to a rapid conversion from a suspended/ nonpolarized to an adherent/polarized cell type, a transition that relies on EphA3 functions operating in the absence of Eph-kinase signaling. Cell morphology change and adhesion of LK63 cells are effectively attenuated by endogenous protein tyrosine phosphatase (PTP) activity, whereby PTP inhibition and productive EphA3-phosphotyrosine signaling reverse the phenotype to nonadherent cells with a condensed cytoskeleton. Our findings suggest that Eph-associated PTP activities not only control receptor phosphorylation levels, but as a result switch the response to ephrin contact from repulsion to adhesion, which may play a role in the pathology of hematopoietic tumors.