Disabled1 regulates the intracellular trafficking of reelin receptors.
Reelin is a huge secreted protein that controls proper laminar formation in the developing brain. It is generally believed that tyrosine phosphorylation of Disabled1 (Dab1) by Src family tyrosine kinases is the most critical downstream event in Reelin signaling. The receptors for Reelin belong to the low density lipoprotein receptor family, most of whose members undergo regulated intracellular trafficking. In this study, we propose novel roles for Dab1 in Reelin signaling. We first demonstrated that cell surface expression of Reelin receptors was decreased in Dab1-deficient neurons. In heterologous cells, Dab1 enhanced cell surface expression of Reelin receptors, and this effect was mediated by direct interaction with the receptors. Moreover, Dab1 did not stably associate with the receptors at the plasma membrane in the resting state. When Reelin was added to primary cortical neurons, Dab1 was recruited to the receptors, and its tyrosine residues were phosphorylated. Although Reelin and Dab1 colocalized well shortly after the addition of Reelin, Dab1 was no longer associated with internalized Reelin. When Src family tyrosine kinases were inhibited, internalization of Reelin was severely abrogated, and Reelin colocalized with Dab1 near the plasma membrane for a prolonged period. Taken together, these results indicate that Dab1 regulates both cell surface expression and internalization of Reelin receptors, and these regulations may play a role in correct laminar formation in the developing brain.
Morimura
Toshifumi
T
Division of Molecular Neurobiology, Department of Basic Medical Science, the Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku 108-8639, Japan. morimura@brain.riken.jp
Hattori
Mitsuharu
M
Ogawa
Masaharu
M
Mikoshiba
Katsuhiko
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019921:Biotinylation; D001921:Brain / Q000196:embryology* / Q000378:metabolism; D019556:COS Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011973:Receptors, LDL / Q000737:chemistry; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015816:Cell Adhesion Molecules, Neuronal; C115785:DAB1 protein, human; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D000091042:Reelin Protein; C469363:reelin receptor; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases