Signaling through Disabled 1 requires phosphoinositide binding.
The Reelin signaling pathway plays a critical role in the correct positioning of neurons within the developing brain. Within this pathway, Disabled 1 (Dab1) serves as an intracellular adaptor that is tyrosine phosphorylated when Reelin, a secreted glycoprotein, binds to the lipoprotein receptors VLDLR and ApoER2 on the surface of neurons. The phosphotyrosine-binding (PTB) domain within its amino terminus enables Dab1 to recognize and bind to a conserved sequence motif within the cytoplasmic tails of the receptors. In addition, the PTB contains a Pleckstrin Homology-like subdomain that binds to phosphoinositides. Here, we show that the phosphoinositide-binding region within Dab1 PTB domain is required for membrane localization and basal tyrosine phosphorylation of Dab1 independently of VLDLR and ApoER2. Furthermore, receptor-independent membrane targeting of Dab1 is required for its interaction with Src and Crk, and disruption of phosphoinositide binding also blocks subsequent Reelin-induced tyrosine phosphorylation of Dab1.
Huang
Yongcheng
Y
Division of Pharmacology, College of Pharmacy, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210, USA.
Shah
Vaibhav
V
Liu
Tongzheng
T
Keshvara
Lakhu
L
D000818:Animals; D001483:Base Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002460:Cell Line; D017931:DNA Primers; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction
D015816:Cell Adhesion Molecules, Neuronal; D017931:DNA Primers; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D010716:Phosphatidylinositols; D000091042:Reelin Protein; D016392:Proto-Oncogene Proteins pp60(c-src); C000717128:Reln protein, mouse; D012697:Serine Endopeptidases