Disease relevance of Dab1

• A distal Dab1 cell had been reported in the FVB/N mouse retina, a model of retinitis pigmentosa (Park et al. [2004] Cell Tissue Res 315:407-412) [1].

Psychiatry related information on Dab1

• Our findings suggest that Dab1 gene disruption sensitizes mice to tau hyperphosphorylation contingent on specific haplotypes that are linked to Alzheimer's disease loci [2].
• The present results extend this evidence by directly implicating Dab-1 in postnatal critical period plasticity of visual cortex [3].

High impact information on Dab1

• The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2-/- cortices [4].
• These results suggest that Reln regulates neuronal positioning by stimulating Dab1 tyrosine phosphorylation [5].
• Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway [6].
• Addition of Reelin interfering antibodies, receptor antagonists, and Dab1 phosphorylation inhibitors prevented dendrite outgrowth from normal neurons, whereas addition of recombinant Reelin rescued the deficit in reeler cultures [6].
• However, in the reeler background, ectopic Reelin induced tyrosine phosphorylation of Dab-1 in the ventricular zone and rescued some, but not all, of the neuroanatomic and behavioral abnormalities characteristic of reeler [7].

Biological context of Dab1

• In contrast, Dab1 is a cytoplasmic protein which has properties of an adapter protein that functions in phosphorylation-dependent intracellular signal transduction [8].
• Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function [9].
• In vivo, absence of Reln correlates with up-regulation of the docking protein Dab1 and decreased Dab1 tyrosine phosphorylation [10].
• 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 [11].
• Reelin stimulates phosphorylation of Dab1 on tyrosines 198 and 220, and phosphorylated Dab1 is likely to interact with downstream signaling proteins that contain Src homology 2 (SH2) domains [12].

Anatomical context of Dab1

• During development, cells expressing Dab1 are located next to those secreting Reln at critical stages of formation of the cerebral cortex, cerebellum and hippocampus, before the first abnormalities in cell position become apparent in either reeler or scrambler [8].
• Cyclin-dependent kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning of facial branchiomotor and inferior olive neurons in the developing mouse hindbrain [13].
• In the double-null mice of p35 and either Dab1 or Reelin, additional migration defects occur in the Purkinje cells in the cerebellum and in the pyramidal neurons in the hippocampus [14].
• Moreover, Dab1 did not stably associate with the receptors at the plasma membrane in the resting state [15].
• Dab1 is a key cytoplasmic mediator in Reelin signaling that controls cell positioning in the developing central nervous system, whereas Dab2 is an adapter protein that plays a role in endocytosis [16].

Associations of Dab1 with chemical compounds

• Although the functional significance of Dab1 serine phosphorylation is unclear, our results suggest that there is biochemical cross-talk between two signaling pathways that control cell positioning [17].
• Dab1 co-localizes with the high-affinity glycine transporter, indicating that these amacrine cells are glycinergic [18].
• Reelin is a secreted glycoprotein that regulates neuronal positioning in cortical brain structures through the VLDLR and ApoER2 receptors and the adaptor protein Dab1 [6].
• Mutated Reelin, which lacks the CR-50 epitope region, cannot form a homopolymer and fails to induce efficient tyrosine phosphorylation of Disabled 1 (Dab1), which should occur to transduce the Reelin signal [19].
• Dab1 molecules lacking phosphotyrosine are not degraded in neurons in which the Dab1 degradation pathway is active [20].

Enzymatic interactions of Dab1

• When fyn copy number is reduced, src, but not yes, becomes important, reflecting a partial redundancy between fyn and src.CONCLUSIONS: Reelin activates Fyn to phosphorylate and downregulate Dab1 during brain development [21].

Regulatory relationships of Dab1

• Binding of Reelin to ApoER2 and VLDLR induces a rapid increase in tyrosine phosphorylation of Dab1, an adaptor protein that associates with the cytoplasmic domain of the receptors [22].
• Using pharmacological inhibitors and mice harboring mutant alleles of Dab1, we show here that tyrosine phosphorylation, but not the carboxyl-terminal region, of Dab1 is required for Reelin-induced activation of Akt and Src family kinases [23].
• Additionally, we detected neurokinin-1 receptors expressed by Dab1-labeled neurons in reeler laminae I-III and the lateral spinal nucleus [24].

Other interactions of Dab1

• We have found that the intracellular Dab1 protein receives a tyrosine phosphorylation signal from extracellular Reln protein [5].
• We have generated mutant mice that express only a natural splice form of Dab1, p45, that lacks the C-terminal region of p80 [25].
• The results were unexpected because Fyn deficiency does not cause the same developmental phenotype as Dab1 or Reelin deficiency [21].
• Overexpression of CrkIIGFP rescued the migration of these cells, suggesting that Dab1 makes Crk a limiting factor for migration [26].
• Reelin binds to transmembrane receptors, including VLDLR and ApoER2, and stimulates tyrosine phosphorylation of Disabled-1 (Dab1), which associates with an NPxY motif present in the cytoplasmic domain of the receptors [18].

Analytical, diagnostic and therapeutic context of Dab1

• Through the techniques of isothermal titration calorimetry (ITC), analysis of Dab1 PTB domain mutants, and nuclear magnetic resonance (NMR), we have evaluated the characteristics of binding of the Dab1 PTB domain to various peptide and PI ligands [27].
• We used immunocytochemistry to map the distribution of Reelin and Disabled-1 (the protein product of the reeler gene, and the intracellular adaptor protein, Dab1, involved in its signaling pathway) in adjacent regions of the developing dorsal horn, from early to late embryonic development [24].
• This study was conducted to characterize Dab1-labeled cells in the guinea pig retina in detail using immunocytochemistry, quantitative analysis, and electron microscopy [28].
• Co-immunoprecipitation experiments and in vitro binding experiments both indicated direct interaction between Siah and Dab1 [29].
• Dab1 mutant mice provide an animal model for studying the relationships between ApoE receptors, tau hyperphosphorylation, and Alzheimer's disease [2].

References