Crk and ABI1: binary molecular switches that regulate abl tyrosine kinase and signaling to the cytoskeleton.
Crk and ABI1: binary molecular switches that regulate abl tyrosine kinase and signaling to the cytoskeleton.
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DOI：
10.1177/1947601912460051
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发表时间：
2012-05-01
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影响因子：
--
通讯作者：
Kotula, Leszek
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文献类型：
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作者：
Hossain, Sajjad;Dubielecka, Patrycja M;Kotula, Leszek
非受体酪氨酸激酶Abl和Arg是人类基因组中最具特征的酪氨酸激酶之一。与bcr(bcr-Abl)或Gag(v-Abl)的N端融合激活Abl分别与慢性粒细胞白血病或Ph+急性淋巴细胞白血病和小鼠白血病病毒有关。此外，几种致癌生长因子受体下游Abl和Arg的异常激活也参与了多种人类癌症的发生和发展，通常与不良的临床结局、耐药性和肿瘤的侵袭和转移有关。ABL的激活可以通过多种机制发生，包括结构域相互作用，包括结构域相互作用，包括自身抑制构象的结构重塑，以及上游激酶和磷酸酶的直接磷酸化。ABL的结构性激活通过调节细胞的黏附、运动和侵袭，在肌动蛋白细胞骨架的调控中起着重要作用。本文综述了Abl和Arg在肿瘤进展中的作用，特别是Crk和Abi1适配器蛋白作为Abl反式激活的不同分子开关所起的作用。这些见解，再加上对这些激酶结构的新见解，为设想Crk和ABI1微调Abl调控以控制细胞骨架信号提供了理论基础。
The nonreceptor tyrosine kinases Abl and Arg are among the most well-characterized tyrosine kinases in the human genome. The activation of Abl by N-terminal fusions with Bcr (Bcr-Abl) or Gag (v-Abl) is responsible for chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia and mouse leukemia virus, respectively. In addition, aberrant Abl and Arg activation downstream of several oncogenic growth factor receptors contributes to the development and progression of a variety of human cancers, often associated with poor clinical outcome, drug resistance, and tumor invasion and metastasis. Abl activation can occur by a variety of mechanisms that include domain interactions involving structural remodeling of autoinhibited conformations as well as direct phosphorylation by upstream kinases and phosphatases. Constitutive activation of Abl plays a significant role in regulating the actin cytoskeleton by modulating cell adhesion, motility, and invadopodia. This review addresses the role of Abl and Arg in tumor progression with particular emphasis on the roles of Crk and Abi1 adapter proteins as distinct molecular switches for Abl transactivation. These insights, combined with new insights into the structure of these kinases, provide the rationale to envision that Crk and Abi1 fine-tune Abl regulation to control signaling to the cytoskeleton.