Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas, Investigación Desarrollo e Innovación Cantabria, Departamento de Biología Molecular, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain.
J Cell Biol. 2010 Nov 29;191(5):967-79. doi: 10.1083/jcb.201004067.
As orchestrators of essential cellular processes like proliferation, ERK1/2 mitogen-activated protein kinase signals impact on cell cycle regulation. A-type lamins are major constituents of the nuclear matrix that also control the cell cycle machinery by largely unknown mechanisms. In this paper, we disclose a functional liaison between ERK1/2 and lamin A whereby cell cycle progression is regulated. We demonstrate that lamin A serves as a mutually exclusive dock for ERK1/2 and the retinoblastoma (Rb) protein. Our results reveal that, immediately after their postactivation entrance in the nucleus, ERK1/2 dislodge Rb from its interaction with lamin A, thereby facilitating its rapid phosphorylation and consequently promoting E2F activation and cell cycle entry. Interestingly, these effects are independent of ERK1/2 kinase activity. We also show that cellular transformation and tumor cell proliferation are dependent on the balance between lamin A and nuclear ERK1/2 levels, which determines Rb accessibility for phosphorylation/inactivation.
作为增殖等重要细胞过程的协调者，ERK1/2 丝裂原活化蛋白激酶信号对细胞周期调控有影响。A 型核纤层蛋白是核基质的主要组成部分，通过很大程度上未知的机制来控制细胞周期机制。在本文中，我们揭示了 ERK1/2 和核纤层蛋白 A 之间的功能联系，通过这种联系调节细胞周期的进展。我们证明核纤层蛋白 A 作为 ERK1/2 和视网膜母细胞瘤（Rb）蛋白的相互排斥 docking 点。我们的结果表明，ERK1/2 在其激活后立即进入细胞核后，会将 Rb 从与核纤层蛋白 A 的相互作用中逐出，从而促进其快速磷酸化，并最终促进 E2F 激活和细胞周期进入。有趣的是，这些效应独立于 ERK1/2 激酶活性。我们还表明，细胞转化和肿瘤细胞增殖依赖于核纤层蛋白 A 和核 ERK1/2 水平之间的平衡，这决定了 Rb 对磷酸化/失活的可及性。
