Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients.
Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients.
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DOI：
10.1038/onc.2009.7
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发表时间：
2009-04-09
期刊：
影响因子：
8
通讯作者：
Arlinghaus RB
中科院分区：
文献类型：
--
作者：
Samanta AK;Chakraborty SN;Wang Y;Kantarjian H;Sun X;Hood J;Perrotti D;Arlinghaus RB
接受甲磺酸伊马替尼（IM）治疗的慢性髓性白血病（CML）患者由于Bcr-Abl激酶结构域内的突变以及其他导致进展至晚期（急变）和林恩酪氨酸激酶表达增加的变化而产生耐药性，但对该激酶的调节尚不清楚。在Bcr-Abl+细胞中，通过Jak 2抑制剂或Jak 2特异性短干扰RNA（siRNA）抑制Bcr-Abl的下游靶点Jak 2降低SET蛋白水平，并增加PP 2A Ser/Thr磷酸酶和Shp 1酪氨酸磷酸酶活性，这导致活化的林恩水平降低。与单独抑制Jak 2相比，PP 2A活化与Jak 2抑制组合增强了活化的林恩激酶的减少。相比之下，抑制PP 2A或Shp 1与抑制Jak 2组合干扰林恩激酶活化的损失比单独抑制Jak 2更大，表明PP 2A和Shp 1参与了由Jak 2抑制引起的林恩激酶的失活。抑制Jak 2诱导的细胞凋亡和减少集落形成IM敏感和耐药Bcr-Abl突变细胞系。Jak 2抑制也诱导急变期患者的CML细胞凋亡，但在正常造血细胞中不诱导凋亡。这些结果表明，林恩位于Jak 2的下游，并且Jak 2通过SET-PP 2A-Shp 1途径维持CML中活化的林恩激酶。
Chronic myelogenous leukemia (CML) patients treated with imatinib mesylate (IM) become drug resistant by mutations within the kinase domain of Bcr–Abl, and by other changes that cause progression to advanced stage (blast crisis) and increased expression of the Lyn tyrosine kinase, the regulation of which is not understood yet. In Bcr–Abl+ cells inhibition of Jak2, a downstream target of Bcr–Abl, by either Jak2 inhibitors or Jak2-specific short interfering RNA (siRNA) reduced the level of the SET protein, and increased PP2A Ser/Thr phosphatase and Shp1 tyrosine phosphatase activities, which led to decreased levels of activated Lyn. Activation of PP2A combined with Jak2 inhibition enhanced the reduction of activated Lyn kinase compared with Jak2 inhibition alone. In contrast, inhibition of either PP2A or Shp1 combined with Jak2 inhibition interfered with the loss of Lyn kinase activation more so than Jak2 inhibition alone, indicating the involvement of PP2A and Shp1 in the inactivation of the Lyn kinase caused by Jak2 inhibition. Inhibition of Jak2 induced apoptosis and reduced colony formation in IM-sensitive and -resistant Bcr–Abl mutant cell lines. Jak2 inhibition also induced apoptosis in CML cells from blast crisis patients but not in normal hematopoietic cells. These results indicate that Lyn is downstream of Jak2, and Jak2 maintains activated Lyn kinase in CML through the SET–PP2A–Shp1 pathway.
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影响因子：
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作者：
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