1. LIM-only protein 4 interacts directly with the repulsive guidance molecule A receptor Neogenin.
- Author
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Schaffar G, Taniguchi J, Brodbeck T, Meyer AH, Schmidt M, Yamashita T, and Mueller BK
- Subjects
- Adaptor Proteins, Signal Transducing, Amides pharmacology, Analysis of Variance, Animals, Cells, Cultured, Cerebral Cortex cytology, Embryo, Mammalian, Enzyme Inhibitors pharmacology, GPI-Linked Proteins, Gene Expression drug effects, Green Fluorescent Proteins biosynthesis, Homeodomain Proteins biosynthesis, Humans, LIM Domain Proteins, Neurites drug effects, Neurites physiology, Neurons cytology, Neurons drug effects, Protein Structure, Tertiary, Pyridines pharmacology, RNA, Small Interfering pharmacology, Rats, Transcription Factors biosynthesis, Transfection methods, Tubulin pharmacology, Two-Hybrid System Techniques, rhoA GTP-Binding Protein genetics, rhoA GTP-Binding Protein metabolism, Homeodomain Proteins metabolism, Membrane Glycoproteins metabolism, Membrane Proteins metabolism, Nerve Tissue Proteins metabolism, Neurons physiology, Transcription Factors metabolism
- Abstract
Repulsive guidance molecule A (RGM A) was recently described as a potent inhibitor of neuroregeneration in a rat spinal cord injury model. The receptor mediating RGM A's repulsive activity was shown to be Neogenin, a member of the Deleted in Colorectal Cancer (DCC) family of netrin receptors. Binding of RGM A to Neogenin induces activation of the small GTPase RhoA and of its effector Rho-kinase by an unknown mechanism. Here we show, that the cytoplasmic tail of Neogenin interacts directly with the transcriptional coactivator LIM domain only 4 (LMO4) in human SH-SY5Y cells, human Ntera neurons, and in embryonic rat cortical neurons. RGM A binding to Neogenin but not binding of Netrin-1, induces release of LMO4 from Neogenin. Down-regulation of LMO4 neutralizes the repulsive activity of RGM A in neuronal cell lines and embryonic rat cortical neurons and prevents RhoA activation. These results show for the first time that an interaction of Neogenin with LMO4 is involved in the RGM A - Neogenin signal transduction pathway for RhoA activation.
- Published
- 2008
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