TY  - JOUR
A1  - Drost, Jessica
A1  - Nonis, David
A1  - Eich, Florian
A1  - Leske, Oliver
A1  - Damrath, Ewa
A1  - Brunt, Ewout R.
A1  - Lastres-Becker, Isabel
A1  - Heumann, Rolf
A1  - Nowock, Joachim
A1  - Auburger, Georg
T1  - Ataxin-2 modulates the levels of Grb2 and Src but not Ras signaling
T2  - Journal of molecular neuroscience
N2  - 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.
Y1  - 2013
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/33351
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-333513
SN  - 0895-8696
SN  - 1559-1166
N1  - 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.
VL  - 51
IS  - 1
SP  - 68
EP  - 81
PB  - Springer
CY  - New York, NY
ER  -