Critical role for lipid raft-associated Src kinases in activation of PI3K-Akt signalling
Critical role for lipid raft-associated Src kinases in activation of PI3K-Akt signalling
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DOI：
10.1016/j.cellsig.2006.12.003
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发表时间：
2007-05-01
影响因子：
4.8
通讯作者：
Seckl, Michael J.
中科院分区：
文献类型：
--
作者：
Arcaro, Alexandre;Aubert, Muriel;Seckl, Michael J.
脂筏是不同于小窝的膜微区，其在多肽生长因子信号传导中的功能仍不清楚。在此我们表明，在小细胞肺癌（SCLC）细胞中，特定的生长因子受体如c - Kit与脂筏相关联，并且这些区域在磷酸肌醇3 - 激酶（PI3K）信号传导的激活中起关键作用。I(A)类p85/p110α在脂筏中与Src相关联，并在体外被Src激活。脂筏的完整性对于Src响应干细胞因子（SCF）的激活至关重要，并且脂筏的破坏选择性地抑制了蛋白激酶B（PKB）/Akt响应SCF刺激的激活。此外，抑制Src激酶可阻断PKB/Akt激活和SCLC细胞生长。使用靶向缺失Src家族激酶基因的成纤维细胞证实了Src激酶在生长因子受体激活PKB/Akt中的作用。此外，Src的一种组成型激活突变体也刺激了脂筏中的PI3K/Akt，表明这些微区在致癌信号传导中起作用。总之，我们的数据表明脂筏通过促进Src与特定PI3K异构体的相互作用，在PI3K信号传导的激活中起关键作用。（c）2006年爱思唯尔公司。保留所有权利。
Lipid rafts are membrane microdomains distinct from caveolae, whose functions in polypeptide growth factor signalling remain unclear. Here we show that in small cell lung cancer (SCLC) cells, specific growth factor receptors such as c-Kit associate with lipid rafts and that these domains play a critical role in the activation of phosphoinositide 3-kinase (PI3K) signalling. The class I(A) p85/p110 alpha associated with Src in lipid rafts and was activated by Src in vitro. Lipid raft integrity was essential for Src activation in response to stein cell factor (SCF) and raft disruption selectively inhibited activation of protein kinase B (PKB)/Akt in response to SCF stimulation. Moreover, inhibition of Src kinases blocked PKB/ Akt activation and SCLC cell growth. The use of fibroblasts with targeted deletion of the Src family kinase genes confirmed the role of Src kinases in PKB/Akt activation by growth factor receptors. Moreover a constitutively activated mutant of Src also stimulated PI3K/Akt in lipid rafts, indicating that these microdomains play a role in oncogenic signalling.Together our data demonstrate that lipid rafts play a key role in the activation of PI3K signalling by facilitating the interaction of Src with specific PI3K isoforms. (c) 2006 Elsevier Inc. All rights reserved.