Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli
Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli
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DOI：
10.1073/pnas.0501196102
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发表时间：
2005-06-28
影响因子：
11.1
通讯作者：
Rambukkana, A
中科院分区：
文献类型：
--
作者：
Tapinos, N;Rambukkana, A
细胞外信号调节激酶（Erk）1/2的激活在多种细胞过程（包括细胞增殖）中起关键作用，已知其由经典的Raf-mitogen-activated protein kinase kinase（MEK）激酶级联介导。哺乳动物细胞中Erk 1/2激活的替代MEK非依赖性信号通路尚不清楚。在研究人原代雪旺氏细胞对麻风分枝杆菌长期感染的反应过程中，我们发现细胞内的麻风分枝杆菌（M。淋巴样细胞激酶（p56 Lck）是一种Src家族成员，通过PKC ε依赖性和MEK非依赖性信号通路直接激活Erk 1/2。该信号传导的激活诱导细胞周期蛋白D1 G（1）/S期进展的核积聚和持续增殖，但不发生转化。因此，我们的数据揭示了一个以前未知的神经胶质细胞增殖的信号传导机制，这可能在去分化以及神经再生和变性中发挥作用。我们的研究结果也可能提供一种潜在的机制，通过这种机制，专性细胞内细菌病原体如M。麻风病破坏神经系统信号传导以繁殖其细胞小生境用于定植和长期细菌存活。
Activation of extracellular signal-regulated kinase (Erk) 1/2, which plays a critical role in diverse cellular processes, including cell proliferation, is known to be mediated by the canonical Raf-mitogen-activated protein kinase kinase (MEK) kinase cascade. Alternative MEK-independent signaling pathways for Erk1/2 activation in mammalian cells are not known. During our studies of human primary Schwann cell response to long-term infection of Mycobacterium leprae, the causative organism of leprosy, we identified that intracellular M. leprae activated Erk1/2 directly by lymphoid cell kinase (p56Lck), a Src family member, by means of a PKC epsilon-dependent and MEK-independent signaling pathway. Activation of this signaling induced nuclear accumulation of cyclin D1 G(1)/S-phase progression, and continuous proliferation, but without transformation. Thus, our data reveal a previously unknown signaling mechanism of glial cell proliferation, which might play a role in dedifferentiation as well as nerve regeneration and degeneration. Our findings may also provide a potential mechanism by which an obligate intracellular bacterial pathogen like M. leprae subverts nervous system signaling to propagate its cellular niche for colonization and long-term bacterial survival.