Serine phosphorylation regulates disabled-1 early isoform turnover independently of Reelin

Abstract

The Reelin-Disabled 1 (Dab1) signaling pathway plays an important role in neuronal cell migration during brain development. Dab1, an intracellular adapter protein which is tyrosine phosphorylated upon Reelin stimulation, has been directly implicated in the transmission and termination of Reelin-mediated signaling. Two main forms of Dab1 have been identified in the developing chick retina, an early isoform (Dab1-E) expressed in progenitor cells and a late isoform (Dab1-L, a.k.a. Dab1) expressed in differentiated cells. Dab1-E is missing two Src family kinase (SFK) phosphorylation sites that are critical for Reelin-Dab1 signaling and is not tyrosine phosphorylated. We have recently demonstrated a role for Dab1-E in the maintenance of retinal progenitor cells. Here, we report that Dab1-E is phosphorylated at serine/threonine residues independent of Reelin. Cdk2, highly expressed in retinal progenitor cells, mediates Dab1-E phosphorylation at serine 475 which in turn promotes ubiquitination-triggered proteasome degradation of Dab1-E. Inhibition of protein phosphatase 1 and/or protein phosphatase 2A leads to increased Dab1-E instability. We propose that Dab1 turnover is regulated by both Reelinindependent serine/threonine phosphorylation and Reelin-dependent tyrosine phosphorylation.

Splice-Mediated Motif Switching Regulates Disabled-1 Phosphorylation and SH2 Domain Interactions

“…In contrast, neither variant 4 nor variant 6 was phosphorylated in the presence of c-Src. These results are in agreement with our previous observations that Dab1-E, the chicken counterpart of variant 6 which lacks exons 7 and 8, is not tyrosine phosphorylated (16,17).…”

Disabled-1 Alternative Splicing in Human Fetal Retina and Neural Tumors

“…These results are in general agreement with previous results in mice and tissue culture [5], [18], [21]. In contrast to Dab1-L which is phosphorylated at tyrosine residues, Dab1-E does not appear to be phosphorylated at the two remaining tyrosine residues but is phosphorylated at multiple serine/threonine residues [22].…”

“…Dab1 is alternatively spliced as a function of developmental stage in chick retina resulting in the formation of two main isoforms: Dab1-E expressed in retinal progenitor cells and Dab1-L expressed in amacrine and ganglion cells [17] . In comparison to the well-characterized Dab1-L isoform, Dab1-E lacks two exons containing two SFK-mediated tyrosine phosphorylation sites and appears to function independently of SFK phosphorylation [22] , [26] . Dab1-E also contains an extra 57 bp exon that is not present in Dab1-L. We used primers flanking the two-exon deletion region (P1, P2) and the insertion region (P3, P4) to determine whether similar alternative splicing events also occur in human fetal retina.…”

“…In comparison to the well-characterized Dab1-L isoform, Dab1-E lacks two exons containing two SFK-mediated tyrosine phosphorylation sites and appears to function independently of SFK phosphorylation [22], [26]. Dab1-E also contains an extra 57 bp exon that is not present in Dab1-L. We used primers flanking the two-exon deletion region (P1, P2) and the insertion region (P3, P4) to determine whether similar alternative splicing events also occur in human fetal retina.…”

Dab1 (Disable Homolog-1) Reelin Adaptor Protein Is Overexpressed in the Olfactory Bulb at Early Postnatal Stages

“…This might represents an alternative role of Dab1 to the Reln pathway, as proposed in the rostral migratory stream cells where Dab1 is triggered by Trombospondin-1 and F-spondin [28] , [29] . Other possibilities could be related to the presence of Dab1 isoforms, similar to those phosphorylated independently of Reln in embryonic retinal cells [30] , [31] or by mechanisms similar to those underlying the GABAergic interneurons layering [32] .…”