Ataxin 10 induces neuritogenesis via interaction with G-protein beta2 subunit.
Spinocerebellar ataxia type 10 (SCA10) is a dominantly inherited disorder caused by an intronic ATTCT pentanucleotide repeat expansion. The ATXN10 gene encodes a novel protein, ataxin 10, known previously as E46L, which is widely expressed in the brain. Ataxin 10 deficiency has been shown recently to cause increased apoptosis in primary cerebellar cultures, thus implicated in SCA10 pathogenesis. The biologic functions of ataxin 10 remain largely unknown. By using yeast-two-hybrid screening of a human brain cDNA library, we identified the G-protein beta2 subunit (Gbeta2) as an ataxin 10 binding partner, and the interaction was confirmed by coimmunoprecipitation and colocalization in mammalian cells in culture. Overexpression of ataxin 10 in PC12 cells induced neurite extension and enhanced neuronal differentiation induced by nerve growth factor (NGF). Moreover, coexpression of ataxin 10 and Gbeta2 potently activated the Ras-MAP kinase-Elk-1 cascade. Dominant negative Ras or inhibitor of MEK-1/2 (U0126) aborted this activation, and blocked morphologic changes, whereas inhibition of TrkA receptor by K252a had no effects. Our data suggest that the ataxin 10-Gbeta2 interaction represents a novel mechanism for inducing neuritogenesis in PC12 cells by activating the Ras-MAP kinase-Elk-1 cascade.
Waragai
Masaaki
M
Department of Neurology, University of Texas Medical Branch, Galveston, Texas 77555-0539, USA.
Nagamitsu
Shinichiro
S
Xu
Weidong
W
Li
Yu Jiang
YJ
Lin
Xi
X
Ashizawa
Tetsuo
T
D000818:Animals; D000067736:Ataxin-10; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D016716:PC12 Cells; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D014162:Transfection; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000067736:Ataxin-10; C496258:Atxn10 protein, rat; D004791:Enzyme Inhibitors; D044387:GTP-Binding Protein beta Subunits; D009419:Nerve Tissue Proteins; D050807:ets-Domain Protein Elk-1; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins