title: Splice-mediated motif switching regulates disabled-1 phosphorylation and SH2 domain interactions.
abstract: Disabled-1 (Dab1) plays a key role in reelin-mediated neuronal migration during brain development. Tyrosine phosphorylation of Dab1 at two YQXI and two YXVP motifs recruits multiple SH2 domains, resulting in activation of a wide range of signaling cascades. However, the molecular mechanisms underlying the coordinated regulation of Dab1 downstream effectors remain poorly understood. Here, we show that alternative splicing results in inclusion of different combinations of YQXI and YXVP motifs in Dab1 isoforms during development. Dab1 variants with partial or complete loss of YQXI motifs are preferentially expressed at early developmental stages, whereas the commonly studied Dab1 is predominantly expressed at late developmental stages. Expression of Dab1 variants in 293T and Neuro2a cells reveals reduced levels or absence of tyrosine phosphorylation in variants that have lost one or both YQXI motifs. We further demonstrate that Dab1 variants differ in their abilities to activate Src and recruit distinct SH2 domains involved in specific downstream signaling pathways. We propose that coordinated expression of specific Dab1 isoforms in different populations of cells in the developing brain contributes to precise neuronal migration by modulating the activity of subsets of Dab1 downstream effectors.
authors.affiliation: Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Gao
authors.forename: Ho Yin
authors.initials: HY
authors.lastname: Poon
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Elena
authors.initials: E
authors.lastname: Palmesino
authors.forename: Darryl D
authors.initials: DD
authors.lastname: Glubrecht
authors.forename: Karen
authors.initials: K
authors.lastname: Colwill
authors.forename: Indrani
authors.initials: I
authors.lastname: Dutta
authors.forename: Artur
authors.initials: A
authors.lastname: Kania
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Roseline
authors.initials: R
authors.lastname: Godbout
mesh_terms: D017398:Alternative Splicing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008959:Models, Neurological; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D017931:DNA Primers; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D000091042:Reelin Protein; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases