Tyrosine phosphorylation of lamin A by Src promotes disassembly of nuclear lamina in interphase

Abstract

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.

Post-Translational Modification of Lamins: Mechanisms and Functions

“…In addition, lamins also have a few tyrosine phosphorylation sites; the epidermal growth factor receptor (EGFR) was reported to phosphorylate lamin A at several tyrosine residues in vitro , including Y45, Y81, Y211, Y359, Y376, Y481, and Y646 ( Tsai et al, 2015 ). Moreover, Scr has been found to be able to regulate the assembly of nuclear lamina by phosphorylating lamin A, especially at Tyr45 ( Chu et al, 2021 ). Lamin functions depend on the capacity for polymerization and depolymerization, in which the phosphorylation contributes to the easily reversible regulation of their ability to form polymers and solubility.…”

“…Another research demonstrated that lamin C was more strongly phosphorylated at Ser22 than lamin A in interphase fibroblasts ( Kolb et al, 2011 ); the reason might be that lamin C was easy to be touched by kinase due to its proximity to the nuclear interior ( Kolb et al, 2011 ). A recent study found abnormal phosphorylation of lamin A at Tyr45 caused the disassembly of lamina in interphase cells by Src ( Chu et al, 2021 ). Ser390, Ser404, Thr424, and Ser652 residues of lamin A are also reported to be phosphorylated during the interphase ( Swift et al, 2013 ).…”

Loss of cell–cell adhesion triggers cell migration through Rac1-dependent ROS generation

“…The plasmid encoding GFP-Src was described previously ( Chu et al, 2021 ). The oxidant-insensitive Src C245A mutant was generated using the QuikChange site-directed mutagenesis kit (Agilent Technologies), and the desired mutation was confirmed by dideoxy DNA sequencing.…”

Mechanobiology of the nucleus during the G2-M transition

“…Whether this holds true for mitotic cell division remains to be determined. Nevertheless, defects in lamin assembly and disassembly were correlated with high levels of aneuploidy, carcinogenesis, and aging [ 132–134 ].…”