Phosphoinositide binding by the disabled-1 PTB domain is necessary for membrane localization and Reelin signal transduction.
Disabled-1 (Dab1) is an essential adaptor protein that functions in the Reelin signaling pathway and is required for the regulation of neuronal migration during embryonic development. Dab1 interacts with NPXY motifs in the cytoplasmic tails of the lipoprotein receptors ApoER2 and very low density lipoprotein receptor through an amino-terminal phosphotyrosine binding (PTB) domain. Binding of Reelin to these receptors leads to tyrosine phosphorylation of Dab1 and the initiation of a signaling cascade that results in remodeling of the cytoskeleton. Structural and biochemical studies of the Dab1 PTB domain have demonstrated that this domain binds to both the NPXY peptide motif in the lipoprotein receptor tails as well as to the head group of phosphoinositide 4,5-P2 through energetically independent mechanisms. Here we have investigated how phosphoinositide binding by the Dab1 PTB domain influences Reelin signal transduction. Our findings in cultured primary neurons that have been transduced with lentiviral constructs expressing mutant Dab1 forms reveal that phosphoinositide binding by the Dab1 PTB domain is necessary for proper membrane localization of Dab1 and for effective transduction of a Reelin signal.
Stolt
Peggy C
PC
Department of Pathology, Harvard Medical School, Brigham and Womens' Hospital, Boston, Massachusetts 02115, USA. peggy.stolt@mpibp-frankfurt.mpg.de
Chen
Ying
Y
Liu
Pingsheng
P
Bock
Hans H
HH
Blacklow
Stephen C
SC
Herz
Joachim
J
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D017353:Gene Deletion; D007700:Kinetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism*; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D000091042:Reelin Protein; D015183:Restriction Mapping; D012697:Serine Endopeptidases; D015398:Signal Transduction
D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D010716:Phosphatidylinositols; D011994:Recombinant Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases