ABSTRACT
Disabled 1 (Dab1) is an adapter protein for very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) and an integral component of the Reelin pathway which orchestrates neuronal layering during embryonic brain development. Activation of Dab1 is induced by binding of Reelin to ApoER2 and VLDLR and phosphorylation of Dab1 mediated by Src family kinases. Here we show that Dab1 also acts as an adaptor for epidermal growth factor receptor (EGFR) and can be phosphorylated by epidermal growth factor (EGF) binding to EGFR. Phosphorylation of Dab1 depends on the kinase activity of EGFR constituting a signal pathway independent of Reelin and its receptors.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Epithelial Cells/metabolism , ErbB Receptors/metabolism , Nerve Tissue Proteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Cell Adhesion Molecules, Neuronal/metabolism , Cell Proliferation , Culture Media, Conditioned/metabolism , Embryo, Mammalian , Epidermal Growth Factor/metabolism , Extracellular Matrix Proteins/metabolism , Female , HEK293 Cells , Humans , Intestinal Mucosa/cytology , Male , Mice , NIH 3T3 Cells , Nerve Tissue Proteins/genetics , Neurons , Phosphorylation , Primary Cell Culture , Reelin Protein , Serine Endopeptidases/metabolism , Signal TransductionABSTRACT
Cancer-associated, loss-of-function mutations in genes encoding subunits of the BRG1/BRM-associated factor (BAF) chromatin-remodeling complexes1-8 often cause drastic chromatin accessibility changes, especially in important regulatory regions9-19. However, it remains unknown how these changes are established over time (for example, immediate consequences or long-term adaptations), and whether they are causative for intracomplex synthetic lethalities, abrogating the formation or activity of BAF complexes9,20-24. In the present study, we use the dTAG system to induce acute degradation of BAF subunits and show that chromatin alterations are established faster than the duration of one cell cycle. Using a pharmacological inhibitor and a chemical degrader of the BAF complex ATPase subunits25,26, we show that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in an almost complete loss of chromatin accessibility at BAF-controlled sites, especially also at superenhancers, providing a mechanism for intracomplex synthetic lethalities.
