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

Kathryn E. Tifft, Katherine A. Bradbury, Katherine L. Wilson

Research output: Contribution to journalArticle

Abstract

X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) is caused by loss of emerin, a nuclear-membrane protein with roles in nuclear architecture, gene regulation and signaling. Phosphoproteomic studies have identified 13 sites of tyrosine phosphorylation in emerin. We validated one study, confirming that emerin is hyper-tyrosine-phosphorylated in Her2-overexpressing cells. We discovered that non-receptor tyrosine kinases Src and Abl each phosphorylate emerin and a related protein, LAP2β, directly. Src phosphorylated emerin specifically at Y59, Y74 and Y95; the corresponding triple Y-to-F ('FFF') mutation reduced tyrosine phosphorylation by ∼70% in vitro and in vivo. Substitutions that removed a single hydroxyl moiety either decreased (Y19F, Y34, Y161F) or increased (Y4F) emerin binding to BAF in cells. Y19F, Y34F, Y161F and the FFF mutant also reduced recombinant emerin binding to BAF from HeLa lysates, demonstrating the involvement of both LEM-domain and distal phosphorylatable tyrosines in binding BAF. We conclude that emerin function is regulated by multiple tyrosine kinases, including Her2, Src and Abl, two of which (Her2, Src) regulate striated muscle. These findings suggest roles for emerin as a downstream effector and 'signal integrator' for tyrosine kinase signaling pathway(s) at the nuclear envelope.

Original languageEnglish (US)
Pages (from-to)3780-3790
Number of pages11
JournalJournal of cell science
Volume122
Issue number20
DOIs
StatePublished - Oct 15 2009

Keywords

  • Abl
  • Barrier-to-autointegration factor(BAF)
  • Breast cancer
  • Cardiomyopathy
  • Emerin
  • Emery-Dreifuss muscular dystrophy
  • Her2
  • LEM domain
  • Laminopathy
  • Neuromuscular junction
  • Nuclear envelope
  • Src

ASJC Scopus subject areas

  • Cell Biology

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