MRL proteins cooperate with activated Ras in glia to drive distinct oncogenic outcomes.
MRL proteins cooperate with activated Ras in glia to drive distinct oncogenic outcomes.
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DOI：
10.1038/onc.2017.68
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发表时间：
2017-07-27
期刊：
影响因子：
8
通讯作者：
Bennett D
中科院分区：
文献类型：
--
作者：
Taylor E;Alqadri N;Dodgson L;Mason D;Lyulcheva E;Messina G;Bennett D
Mig10/RIAM/Lpd （MRL）适配蛋白Lpd通过与Scar/WAVE和Ena/VASP蛋白相互作用调节肌动蛋白动力学，促进细胞突起的形成，刺激侵袭性迁移。然而，MRL蛋白与多种肌动蛋白调节因子相互作用并促进血清反应因子（SRF）信号传导的能力提出了MRL蛋白是否采用替代下游机制以上下文依赖的方式驱动致癌过程的问题。通过果蝇模型，我们发现过表达人类Lpd或其同源的果蝇Pico可以促进rasv12诱导的大脑细胞肿瘤的生长和侵袭。值得注意的是，影响仅限于两种repo阳性胶质细胞群体：侵袭性群体，其特征是依赖JNK的Mmp1表达升高，以及缺乏JNK信号升高的超增殖群体。JNK激活不是由反应性免疫细胞信号触发的，这暗示了内在应激反应的参与。促进rasv12诱导肿瘤传播的能力是由一组肌动蛋白调节因子共享的，其中最突出的是与Pico直接相互作用的Chicadee/Profilin，以及对G:F肌动蛋白动力学变化作出反应的血清反应因子的辅助因子Mal。Mal活性的抑制部分削弱了pico促进RasV12肿瘤侵袭的能力。此外，我们发现幼虫胶质细胞的血清反应因子表达丰富，这解释了胶质细胞对Pico/RasV12过表达的明显敏感性。综上所述，我们的研究结果表明，MRL蛋白与致癌Ras协同促进神经胶质肿瘤的形成，并且在这种情况下，Mal/血清反应因子激活对肿瘤传播具有限速作用。
The Mig10/RIAM/Lpd (MRL) adapter protein Lpd regulates actin dynamics through interactions with Scar/WAVE and Ena/VASP proteins to promote the formation of cellular protrusions and to stimulate invasive migration. However, the ability of MRL proteins to interact with multiple actin regulators and to promote serum response factor (SRF) signalling has raised the question of whether MRL proteins employ alternative downstream mechanisms to drive oncogenic processes in a context-dependent manner. Here, using a Drosophila model, we show that overexpression of either human Lpd or its Drosophila orthologue Pico can promote growth and invasion of RasV12-induced cell tumours in the brain. Notably, effects were restricted to two populations of Repo-positive glial cells: an invasive population, characterized by JNK-dependent elevation of Mmp1 expression, and a hyperproliferative population lacking elevated JNK signalling. JNK activation was not triggered by reactive immune cell signalling, implicating the involvement of an intrinsic stress response. The ability to promote dissemination of RasV12-induced tumours was shared by a subset of actin regulators, including, most prominently, Chicadee/Profilin, which directly interacts with Pico, and, Mal, a cofactor for serum response factor that responds to changes in G:F actin dynamics. Suppression of Mal activity partially abrogated the ability of pico to promote invasion of RasV12 tumours. Furthermore, we found that larval glia are enriched for serum response factor expression, explaining the apparent sensitivity of glial cells to Pico/RasV12 overexpression. Taken together, our findings indicate that MRL proteins cooperate with oncogenic Ras to promote formation of glial tumours, and that, in this context, Mal/serum response factor activation is rate-limiting for tumour dissemination.
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影响因子：
4.5
作者：
Ciurciu A;Duncalf L;Jonchere V;Lansdale N;Vasieva O;Glenday P;Rudenko A;Vissi E;Cobbe N;Alphey L;Bennett D
通讯作者：
Bennett D
影响因子：
8
作者：
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Uhlirova, Mirka
影响因子：
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作者：
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通讯作者：
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