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Identification and characterization of mErk5-T, a novel Erk5/Bmk1 splice variant

B J McCaw1, S Y Chow, E S M Wong

  • 1Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore.

Gene
|February 18, 2005
PubMed

Insights

A novel splice variant of Extracellular Regulated Kinase 5 (ERK5), termed ERK5-T, lacks key functional domains due to alternative intron 4 splicing. This variant retains ERK5 in the cytoplasm, impacting cellular signaling pathways.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Genetics

Background:

  • Extracellular Regulated Kinase 5 (ERK5) is a large MAP kinase crucial for cell proliferation, differentiation, and survival.
  • Previous studies identified ERK5 splice variants (mErk5-a, -b, -c) lacking kinase domains, which can negatively regulate full-length ERK5 function.

Purpose of the Study:

  • To identify and characterize a new murine ERK5 splice variant and its human ortholog.
  • To investigate the functional consequences of this novel variant on ERK5 signaling.

Main Methods:

  • Identification of a novel murine ERK5 splice variant (ERK5-T) and its human ortholog through analysis of alternative splicing of intron 4.
  • Experimental characterization including co-expression with active MEK5, co-immunoprecipitation, and cellular localization studies in HeLaS3 cells.

Main Results:

  • The alternative splicing of intron 4 in ERK5-T results in a premature stop codon, producing a protein lacking the nuclear localization signal (NLS) and proline-rich region (PR).
  • Activated ERK5-T is phosphorylated and can co-immunoprecipitate with ERK5 but fails to translocate to the nucleus, retaining active ERK5 in the cytoplasm.
  • This cytoplasmic retention of active ERK5 by ERK5-T suggests a novel regulatory mechanism.

Conclusions:

  • Alternative RNA processing, specifically alternative splicing of intron 4, generates ERK5 variants that modulate ERK5 signaling.
  • The novel ERK5-T variant contributes to ERK5 regulation by sequestering active ERK5 in the cytoplasm.
  • These findings highlight the importance of RNA processing in controlling ERK5 signaling pathways.

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