JAK-STAT signaling activated by Abl oncogenes
JAK-STAT signaling activated by Abl oncogenes
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DOI：
10.1038/sj.onc.1203484
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发表时间：
2000-05-15
期刊：
影响因子：
8
通讯作者：
Rothman, P
中科院分区：
文献类型：
--
作者：
Danial, NN;Rothman, P
Abl癌蛋白v-Abl和BCR-Abl可以激活信号转导和转录激活因子（STAT）家族的成员。这些癌蛋白激活STAT的机制似乎不同。在由v-Abl转化的细胞中，Janus激酶（JAK）酪氨酸激酶被组成性激活。在这些细胞中，v-Abl癌蛋白和JAK激酶物理结合。v-Abl中JAK相互作用结构域的定位表明v-Abl的羧基末端区域内的氨基酸通过直接相互作用结合JAK。缺乏该区域的v-Abl突变体在体内不结合或激活JAK 1，不能激活STAT蛋白，不诱导细胞增殖，并且在细胞转化中效率较低。JAK 1的激酶失活突变体抑制v-Abl激活STAT、诱导非依赖于精氨酸的增殖和转化骨髓细胞的能力。有趣的是，这些效应与v-AbI激活包括Akt、PI 3-激酶、STAT和Ras在内的几种途径的缺陷相关。这些数据表明，Jak激酶可能在v-AbI诱导的转化中起重要作用。
The Abl oncoproteins v-Abl and BCR-Abl can activate member of the signal transducers and activators of transcription (STAT) family of signaling proteins. The mechanisms by which these oncoproteins activate STATs appear to differ, In cells transformed by v-Abl, Janus kinase (JAK) tyrosine kinases are constitutively activated. Tn these cells, the v-Abl oncoprotein and the JAK kinases physically associate. Mapping of the JAK interaction domain in v-Abl demonstrates that amino acids within the carboxyl terminal region of v-Abl bind JAKs through a direct interaction. A mutant of v-Abl lacking this region does not bind or activate JAK 1 in vivo, fails to activate STAT proteins, does not induce cellular proliferation, and is less efficient in cellular transformation. Kinase inactive mutants of JAK 1 inhibit the ability of v-Abl to activate STATs, to induce cytokine-independent proliferation, and to transform bone marrow cells. Interestingly, these effects correlate with defects in the activation of several pathways by v-AbI including Akt, PI3-kinase, STATs, and Ras, These data suggest that Jak kinases may play an important role in v-Abl induced transformation.