Thrombopoietin signal transduction in purified murine megakaryocytes
Thrombopoietin signal transduction in purified murine megakaryocytes
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DOI：
10.1182/blood.v89.2.483
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发表时间：
1997-01-15
期刊：
影响因子：
20.3
通讯作者：
Kaushansky, K
中科院分区：
文献类型：
--
作者：
Drachman, JG;Sabath, DF;Kaushansky, K
血小板生成素(TPO)是一种新近克隆的细胞因子，可与其受体MPI结合，促进造血细胞的扩增和成熟，主要是巨核细胞系。负责这些事件的信号通路被认为涉及Janus家族的非受体酪氨酸激酶(JAKs)和信号转导和转录激活因子(STATs)，它们被酪氨酸磷酸化激活。之前的研究人员已经在工程和自然产生的细胞系中研究了这些分子。为了研究TPO信号转导更具生理性的分子基础，我们测定了纯化的正常尿巨核细胞中JAK和STAT的激活模式。将这些结果与已建立的只对TPO反应而增殖(BA/F3-MMPL和DA-1-TPO)或仅分化(L8057)的细胞系进行了比较。根据这些发现，提出了一个模型来解释JAK2、TYK2、STAT3和STAT5在TPO信号转导中的生理作用。此外，扩展了先前关于MPI和JAK之间物理相互作用的研究，表明JAK2和TYK2与TPO受体的关联不同。最后，我们发现，在细胞系BA/F3-MMPL中，密切相关的蛋白STAT5A和STAT5B都可以被TPO刺激激活，并能够异源二聚化。总而言之，这些结果进一步加深了我们对巨核细胞和血小板发育早期阶段的理解。(C)1997年由美国血液病学会主办。
Thrombopoietin (TPO) is a recently cloned cytokine that binds to its receptor, MpI, and promotes hematopoietic expansion and maturation, primarily of the megakaryocyte lineage. The signaling pathways responsible for these events are thought to involve the Janus family of nonreceptor tyrosine kinases (JAKs) and the signal transducers and activators of transcription (STATs), which are activated by tyrosine phosphorylation. Previous investigators have studied these molecules in engineered and naturally occurring cell lines. To investigate the molecular basis for TPO signal transduction in a more physiologic target, we determined the pattern of JAK and STAT activation in purified, normal urine megakaryocytes. These results are compared with those of established cell lines that only proliferate (Ba/F3-mMPL and DA-1-TPO) or only differentiate (L8057) in response to TPO. From these findings, a model is proposed to explain the physiologic roles of JAK2, TYK2, STAT3, and STAT5 in TPO signaling. Furthermore, previous studies of the physical interaction between MpI and the JAKs are extended, showing a difference in the association of JAK2 and TYK2 with the TPO receptor. Finally, we show that, in the cell line Ba/F3-mMPL, the closely related proteins STAT5A and STAT5B are both activated by TPO stimulation and are capable of heterodimerization. Together, these results further our understanding of the early stages of megakaryocyte and platelet development. (C) 1997 by The American Society of Hematology.