LIM-only protein 4 interacts directly with the repulsive guidance molecule A receptor Neogenin.
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.
Schaffar
Gregor
G
Neuroscience Research, Abbott GmbH and Company KG, Ludwigshafen, Germany.
Taniguchi
Junko
J
Brodbeck
Tanja
T
Meyer
Axel H
AH
Schmidt
Martin
M
Yamashita
Toshihide
T
Mueller
Bernhard K
BK
D048868:Adaptor Proteins, Signal Transducing; D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058851:GPI-Linked Proteins; D015870:Gene Expression / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000577:Amides; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C114905:LMO4 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011725:Pyridines; C502259:RGM protein, rat; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014404:Tubulin; C485184:enhanced green fluorescent protein; C091279:neogenin; C108830:Y 27632; D049452:Green Fluorescent Proteins; D020742:rhoA GTP-Binding Protein