title: Ataxin-2 modulates the levels of Grb2 and SRC but not ras signaling.
abstract: 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.
authors: Section Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd Floor, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
authors: Jessica
authors: J
authors: Drost
authors: David
authors: D
authors: Nonis
authors: Florian
authors: F
authors: Eich
authors: Oliver
authors: O
authors: Leske
authors: Ewa
authors: E
authors: Damrath
authors: Ewout R
authors: ER
authors: Brunt
authors: Isabel
authors: I
authors: Lastres-Becker
authors: Rolf
authors: R
authors: Heumann
authors: Joachim
authors: J
authors: Nowock
authors: Georg
authors: G
authors: Auburger
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000067528:Ataxins; D001665:Binding Sites; D049109:Cell Proliferation; D004705:Endocytosis; D005347:Fibroblasts / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000067528:Ataxins; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D009419:Nerve Tissue Proteins; D019061:src-Family Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D018631:ras Proteins