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Ataxin-2 modulates the levels of Grb2 and SRC but not ras signaling

Jessica Drost1, David Nonis, Florian Eich

  • 1Section Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd Floor, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.

Journal of Molecular Neuroscience : MN
|January 22, 2013
PubMed

Insights

Ataxin-2 (ATXN2) influences cell growth by interacting with proteins like Grb2 and Src, affecting receptor tyrosine kinase signaling. Its absence or mutations alter protein levels, impacting neuronal health and potentially contributing to diseases like ALS and SCA2.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Neuroscience

Background:

  • Ataxin-2 (ATXN2) is involved in mRNA processing and associates with receptor tyrosine kinases (RTKs).
  • ATXN2 interaction with Src inhibits RTK endocytosis via proline-rich domains (PRD) and SH3 motifs.
  • Gain of function mutations in ATXN2 cause spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS), while knockout leads to hypertrophy and insulin resistance.

Purpose of the Study:

  • To investigate the influence of ATXN2 on trophic regulation by surveying its interactions with SH3-containing proteins.
  • To elucidate the role of ATXN2 in the context of RTK endocytosis and its impact on cell proliferation and signaling.

Main Methods:

  • Surveyed ATXN2 interactions with SH3 motifs, identifying a novel interaction with Grb2.
  • Utilized glutathione S-transferase (GST) pull-down assays and coimmunoprecipitation to confirm ATXN2-Grb2 binding.
  • Analyzed protein and transcript levels of ATXN2, Grb2, and Src in SCA2 patient fibroblasts and ATXN2 knockout (KO) mouse models (embryonal fibroblasts and postmitotic neurons).

Main Results:

  • Confirmed a physiologically relevant association between ATXN2 and Grb2.
  • Observed diminished Grb2 and Src protein levels in SCA2 fibroblasts and KO MEFs, with transcript upregulation suggesting increased turnover.
  • Found that ATXN2 absence alone did not significantly alter Grb2-dependent Ras/ERK signaling but decreased Src levels in KO neurons.

Conclusions:

  • ATXN2 mutations modulate components of the RTK endocytosis complex.
  • These modulations may contribute to altered cell proliferation, translation, and growth observed in ATXN2-related disorders.
  • The study highlights ATXN2's complex role in regulating RTK signaling pathways and cellular homeostasis.

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