ACTIVATION OF TYROSINE KINASE AND MICROFILAMENT-BINDING FUNCTIONS OF C-ABL BY BCR SEQUENCES IN BCR/ABL FUSION PROTEINS
ACTIVATION OF TYROSINE KINASE AND MICROFILAMENT-BINDING FUNCTIONS OF C-ABL BY BCR SEQUENCES IN BCR/ABL FUSION PROTEINS
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DOI：
10.1128/mcb.11.3.1553
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发表时间：
1991-03-01
影响因子：
5.3
通讯作者：
WANG, JYJ
中科院分区：
文献类型：
--
作者：
MCWHIRTER, JR;WANG, JYJ
慢性粒细胞白血病和一种类型的急性淋巴细胞白血病的特征是9;22染色体易位，其中bcr基因的5'序列与c-abl原癌基因融合。 由此产生的嵌合基因编码bcr/abl融合蛋白，其具有去调节的酪氨酸激酶活性，并且似乎在这些白血病的诱导中起重要作用。 构建了一系列bcr/abl基因，其中bcr基因的巢式缺失与c-abl基因融合。 这些基因编码的融合蛋白进行了体内自磷酸化和亚细胞定位的差异。 我们的研究结果表明bcr序列激活c-abl的两种功能：酪氨酸激酶活性和一种以前未描述的微生物活性结合功能。 bcr的两个不同程度激活这些功能的区域已经被定位：氨基酸1到63是强激活的，氨基酸64到509是弱激活的。 酪氨酸激酶和微丝结合功能并不相互依赖，因为激酶缺陷型bcr/abl突变体仍然与肌动蛋白丝相关，而缺乏肌动蛋白结合的bcr/abl突变体仍然具有失调的激酶活性。 bcr/abl酪氨酸激酶对肌动蛋白丝功能的修饰可能是白血病发生中的一个重要事件。
Chronic myelogenous leukemia and one type of acute lymphoblastic leukemia are characterized by a 9;22 chromosome translocation in which 5' sequences of the bcr gene become fused to the c-abl proto-oncogene. The resulting chimeric genes encode bcr/abl fusion proteins which have deregulated tyrosine kinase activity and appear to play an important role in induction of these leukemias. A series of bcr/abl genes were constructed in which nested deletions of the bcr gene were fused to the c-abl gene. The fusion proteins encoded by these genes were assayed for autophosphorylation in vivo and for differences in subcellular localization. Our results demonstrate that bcr sequences activate two functions of c-abl: the tyrosine kinase activity and a previously undescribed microfilament-binding function. Two regions of bcr which activate these functions to different degrees have been mapped: amino acids 1 to 63 were strongly activating and amino acids 64 to 509 were weakly activating. The tyrosine kinase and microfilament-binding functions were not interdependent, as a kinase defective bcr/abl mutant still associated with actin filaments and a bcr/abl mutant lacking actin association still had deregulated kinase activity. Modification of actin filament functions by the bcr/abl tyrosine kinase may be an important event in leukemogenesis.