Stimulation of NeuroD Activity by Huntingtin and Huntingtin-Associated Proteins HAP1 and MLK2

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 16; pp. 9578 - 9583
• Main Authors: Marcora, Edoardo, Gowan, Katherine, Lee, Jacqueline E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05-08-2003; National Acad Sciences
• Subjects: Alkaline Phosphatase - metabolism; Amino acids; Animals; Antibodies; Basic Helix-Loop-Helix Transcription Factors; Biological Sciences; Carbon-Oxygen Lyases - metabolism; Cell Survival; DNA - metabolism; DNA, Complementary - metabolism; DNA-(Apurinic or Apyrimidinic Site) Lyase; Embryos; Epitopes; Gene Deletion; Genetics; Humans; Huntingtin Protein; huntingtin-associated protein 1; Huntington Disease - metabolism; Immunoblotting; MAP Kinase Kinase Kinases - metabolism; Mice; mixed lineage kinase 2; Models, Biological; Molecular biology; Nerve Tissue Proteins - metabolism; NeuroD protein; Neurogenesis; Neurology; Neurons; Neurons - metabolism; Nuclear Proteins - metabolism; Phosphorylation; Plasmids; Point Mutation; Protein Binding; Protein Structure, Tertiary; Proteins; RNA, Messenger - metabolism; Transcription, Genetic; Transfection; Tumor Cells, Cultured; Two-Hybrid System Techniques; Xenopus; Xenopus Proteins; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1133382100

NeuroD (ND) is a basic helix-loop-helix transcription factor important for neuronal development and survival. By using a yeast two-hybrid screen, we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2), both of which are known to interact with huntingtin (Htt). Htt is a ubiquitous protein important for neuronal transcription, development, and survival, and loss of its function has been implicated in the pathogenesis of Huntington's disease, a neurodegenerative disorder. However, the mechanism by which Htt exerts its neuron-specific function at the molecular level is unknown. Here we report that Htt interacts with ND via HAP1, and that MLK2 phosphorylates and stimulates the activity of ND. Furthermore, we show that Htt and HAP1 facilitate the activation of ND by MLK2. To our knowledge, ND is the first example of a neuron-specific transcription factor involved in neuronal development and survival whose activity is modulated by Htt. We propose that Htt, together with HAP1, may function as a scaffold for the activation of ND by MLK2.