一个紧密连接相关的 Merlin-angiomotin 复合物介导 Merlin 对有丝分裂信号和肿瘤抑制功能的调节。
A tight junction-associated Merlin-angiomotin complex mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions.
机构信息
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
出版信息
Cancer Cell. 2011 Apr 12;19(4):527-40. doi: 10.1016/j.ccr.2011.02.017.
Abstract
The Merlin/NF2 tumor suppressor restrains cell growth and tumorigenesis by controlling contact-dependent inhibition of proliferation. We have identified a tight-junction-associated protein complex comprising Merlin, Angiomotin, Patj, and Pals1. We demonstrate that Angiomotin functions downstream of Merlin and upstream of Rich1, a small GTPase Activating Protein, as a positive regulator of Rac1. Merlin, through competitive binding to Angiomotin, releases Rich1 from the Angiomotin-inhibitory complex, allowing Rich1 to inactivate Rac1, ultimately leading to attenuation of Rac1 and Ras-MAPK pathways. Patient-derived Merlin mutants show diminished binding capacities to Angiomotin and are unable to dissociate Rich1 from Angiomotin or inhibit MAPK signaling. Depletion of Angiomotin in Nf2(-/-) Schwann cells attenuates the Ras-MAPK signaling pathway, impedes cellular proliferation in vitro and tumorigenesis in vivo.
摘要
Merlin/NF2 肿瘤抑制因子通过控制接触依赖性的增殖抑制来抑制细胞生长和肿瘤发生。我们已经鉴定出一个紧密连接相关的蛋白质复合物，包含 Merlin、Angiomotin、Patj 和 Pals1。我们证明 Angiomotin 作为 Rac1 的一个正向调节因子，在 Merlin 下游和 Rich1 上游起作用，Rich1 是一种小 GTP 酶激活蛋白。Merlin 通过与 Angiomotin 的竞争性结合，从 Angiomotin 抑制复合物中释放出 Rich1，使 Rich1 能够使 Rac1 失活，最终导致 Rac1 和 Ras-MAPK 途径的衰减。源自患者的 Merlin 突变体显示出与 Angiomotin 的结合能力降低，并且无法将 Rich1 从 Angiomotin 上解离或抑制 MAPK 信号。在 Nf2(-/-) Schwann 细胞中耗尽 Angiomotin 会减弱 Ras-MAPK 信号通路，阻碍体外细胞增殖和体内肿瘤发生。
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