other neurological disorders. Reelin expression is regulated epigenetically, and transcriptionally by thyroid hormone and, along with NMDA (N-methyl-D-aspartate) receptor subunits, by nuclear proteins CASK, CINAP and Tbr-1. The two best-studied receptors for Reelin are the apolipoprotein E receptor 2 (ApoER2; Lrp8) and the very low density lipoprotein receptor (VLDLR). Competing ligands for these receptors, such as ApoE and RAP, can interfere with Reeling signaling. The secreted glycoprotein Reelin is processed, probably by metalloproteases, into fragments less effective at signaling. Acting as an oligomer, full-length Reelin more effectively binds to the high-affinity receptors ApoER2 and VLDLR, causing clustering. This causes the membrane- and receptor-associated cytosolic Disabled-1 (Dab1) adapter protein to be tyrosine-phosphorylated by src-family kinases such as Fyn. Reelin-induced phosphorylated Dab1 (Dab1-P) stimulates further Src kinase activation, as well as a phosphatidylinositol 3-kinase (PI3K) pathway that activates protein kinase B (Akt) and inhibits glycogen synthase kinase-3beta,which is involved in modulating antiapoptotic, neuroprotective pathways of cell growth and survival.  Stimulation of the PI3K pathway also results in reduced phosphorylation of Tau protein, involved in microtubule organization. Dab1-P can alternatively signal through Lis1 (Pafah1b1) and the alpha subunits of the Pafah1b complex to control CNS layer formation. Fine tuning of Reelin signaling may occur via phosphorylation-dependent ubiquitination of Dab1-P, thought to be associated with endocytosis of the reeling signaling complex and receptor recycling. There is evidence that alpha3beta1 integrins (Itga3, Itgb1) are also involved alongside ApoER2s and VLDLRs in transmitting Reelin signals to control neuronal positioning. Cadherin-related neuronal receptors bind Reelin and Src kinases as well, and serve as functional Reelin receptors. In adults, Reelin is thought to mediate synaptic plasticity , memory and learning  through Dab1-P, via src kinases and NMDA receptors (e. g. Grin2a, Grin2b), or via PI3K and tetrameric AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptors (e. g. Gria1). To access the ontology report for annotations, GViewer and downloads, click here...(less)