Lamins form the nuclear lamina, which is important for nuclear structure and activity. Although posttranslational modifications, in particular serine phosphorylation, have been shown to be important for structural properties and functions of lamins, little is known about the role of tyrosine phosphorylation in this regard. In this study, we found that the constitutively active Src Y527F mutant caused the disassembly of lamin A/C. We demonstrate that Src directly phosphorylates lamin A mainly at Tyr45 both in vitro and in intact cells. The phosphomimetic Y45D mutant was diffusively distributed in the nucleoplasm and failed to assemble into the nuclear lamina. Depletion of lamin A/C in HeLa cells induced nuclear dysmorphia and genomic instability as well as increased nuclear plasticity for cell migration, all of which were partially restored by re-expression of lamin A, but further promoted by the Y45D mutant. Together, our results reveal a novel mechanism for regulating the assembly of nuclear lamina through Src and suggest that aberrant phosphorylation of lamin A by Src may contribute to nuclear dysmorphia, genomic instability, and nuclear plasticity.

中文翻译：

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Src 对核纤层蛋白 A 的酪氨酸磷酸化促进间期核纤层的分解。

层粘连蛋白形成核层，这对核结构和活动很重要。尽管翻译后修饰，特别是丝氨酸磷酸化，已被证明对核纤层蛋白的结构特性和功能很重要，但对酪氨酸磷酸化在这方面的作用知之甚少。在这项研究中，我们发现组成型活性 Src Y527F 突变体导致核纤层蛋白 A/C 的分解。我们证明 Src 在体外和完整细胞中主要在 Tyr45 处直接磷酸化核纤层蛋白 A。拟磷 Y45D 突变体广泛分布在核质中，无法组装到核层中。HeLa 细胞中核纤层蛋白 A/C 的消耗导致核畸形和基因组不稳定性以及细胞迁移的核可塑性增加，所有这些都因核纤层蛋白 A 的重新表达而部分恢复，但由 Y45D 突变体进一步促进。总之，我们的研究结果揭示了一种通过 Src 调节核纤层组装的新机制，并表明 Src 对纤层蛋白 A 的异常磷酸化可能导致核畸形、基因组不稳定性和核可塑性。