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Tyrosine phosphorylation of nuclear-membrane protein emerin by Src, Abl and other kinases

Kathryn E Tifft1, Katherine A Bradbury, Katherine L Wilson

  • 1Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Journal of Cell Science
|October 1, 2009
PubMed

Insights

Emerin, a protein linked to Emery-Dreifuss muscular dystrophy, is regulated by tyrosine phosphorylation. This phosphorylation affects emerin

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) results from the loss of emerin, a nuclear-membrane protein crucial for nuclear architecture, gene regulation, and signaling.
  • Emerin has 13 identified sites of tyrosine phosphorylation, suggesting a regulatory role for this post-translational modification.

Purpose of the Study:

  • To investigate the role of tyrosine phosphorylation in regulating emerin function.
  • To identify the specific tyrosine kinases that phosphorylate emerin and their impact on emerin's interaction with other proteins.

Main Methods:

  • Validation of previous phosphoproteomic studies on emerin.
  • In vitro and in vivo phosphorylation assays using non-receptor tyrosine kinases Src and Abl.
  • Site-directed mutagenesis (Y-to-F substitutions) to assess the impact of specific tyrosine residues on phosphorylation and BAF binding.

Main Results:

  • Emerin is hyper-phosphorylated in Her2-overexpressing cells, and Src and Abl directly phosphorylate emerin.
  • Src specifically phosphorylates emerin at Y59, Y74, and Y95; a triple Y-to-F mutant significantly reduced tyrosine phosphorylation.
  • Mutations in specific tyrosine residues (Y19F, Y34F, Y161F) and the triple FFF mutant reduced emerin binding to BAF, indicating the importance of both LEM-domain and distal tyrosines.

Conclusions:

  • Emerin function is modulated by multiple tyrosine kinases, including Her2, Src, and Abl.
  • Emerin acts as a signaling integrator at the nuclear envelope for tyrosine kinase pathways.
  • These findings provide insights into the molecular mechanisms underlying EDMD and the role of emerin in striated muscle regulation.

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