Serine phosphorylation regulates disabled-1 early isoform turnover independently of Reelin.
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 Reelin-independent serine/threonine phosphorylation and Reelin-dependent tyrosine phosphorylation.
Department of Oncology, School of Cancer, Engineering and Imaging Sciences, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2.
Zhihua
Z
Gao
Roseline
R
Godbout
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D002460:Cell Line; D002642:Chick Embryo; D051357:Cyclin-Dependent Kinase 2 / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D055550:Protein Stability; D000091042:Reelin Protein; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000502:physiology; D012694:Serine / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D000091042:Reelin Protein; D012694:Serine; D051357:Cyclin-Dependent Kinase 2; C000717127:RELN protein, human; D012697:Serine Endopeptidases