Ataxin-2 modulates the levels of Grb2 and Src but not Ras signaling

  • Ataxin-2 (ATXN2) is implicated mainly in mRNA processing. Some ATXN2 associates with receptor tyrosine kinases (RTK), inhibiting their endocytic internalization through interaction of proline-rich domains (PRD) in ATXN2 with SH3 motifs in Src. Gain of function of ATXN2 leads to neuronal atrophy in the diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Conversely, ATXN2 knockout (KO) mice show hypertrophy and insulin resistance. To elucidate the influence of ATXN2 on trophic regulation, we surveyed interactions of ATXN2 with SH3 motifs from numerous proteins and observed a novel interaction with Grb2. Direct binding in glutathione S-transferase (GST) pull-down assays and coimmunoprecipitation of the endogenous proteins indicated a physiologically relevant association. In SCA2 patient fibroblasts, Grb2 more than Src protein levels were diminished, with an upregulation of both transcripts suggesting enhanced protein turnover. In KO mouse embryonal fibroblasts (MEF), the protein levels of Grb2 and Src were decreased. ATXN2 absence by itself was insufficient to significantly change Grb2-dependent signaling for endogenous Ras levels, Ras-GTP levels, and kinetics as well as MEK1 phosphorylation, suggesting that other factors compensate for proliferation control. In KO tissue with postmitotic neurons, a significant decrease of Src protein levels is prominent rather than Grb2. ATXN2 mutations modulate the levels of several components of the RTK endocytosis complex and may thus contribute to alter cell proliferation as well as translation and growth.

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Metadaten
Author:Jessica Drost, David Nonis, Florian Eich, Oliver Leske, Ewa Damrath, Ewout R. Brunt, Isabel Lastres-Becker, Rolf Heumann, Joachim Nowock, Georg AuburgerORCiDGND
URN:urn:nbn:de:hebis:30:3-333513
DOI:https://doi.org/10.1007/s12031-012-9949-4
ISSN:0895-8696
ISSN:1559-1166
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/23335000
Parent Title (German):Journal of molecular neuroscience
Publisher:Springer
Place of publication:New York, NY
Document Type:Article
Language:English
Date of Publication (online):2013/01/19
Date of first Publication:2013/01/19
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2014/04/03
Volume:51
Issue:1
Page Number:14
First Page:68
Last Page:81
Note:
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
HeBIS-PPN:364409657
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universit├Ątspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0