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THE ROLE OF THE PTB DOMAIN IN REGULATION OF DAB1 PHOSPHORYLATION
Author(s) -
Huang Yongcheng,
Shah Vaibhav,
Keshvara Lakhu
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a241-c
Subject(s) - dab1 , reelin , phosphorylation , microbiology and biotechnology , signal transducing adaptor protein , phosphotyrosine binding domain , tyrosine phosphorylation , signal transduction , immunoreceptor tyrosine based activation motif , receptor tyrosine kinase , low density lipoprotein receptor related protein 8 , proto oncogene tyrosine protein kinase src , sh2 domain , biology , receptor , chemistry , biochemistry , very low density lipoprotein , lipoprotein , cholesterol
The Reelin signaling pathway is critical for proper positioning of neurons during normal mammalian brain development. Reelin, a secreted glycoprotein, serves as a ligand for the lipoprotein receptors VLDLR and ApoER2 and mediates its effects through the adapter protein Dab1, which binds to the cytoplasmic tails of the receptors. The hallmark feature of this pathway is Reelin‐induced phosphorylation of Dab1 on multiple tyrosine residues by Src family kinases. This tyrosine phosphorylation is critical to this pathway as it enables Dab1 to mediate downstream signaling by recruiting Src homology 2 (SH2) domain containing proteins. Given that all known cellular effects of Reelin are dependent on Dab1, it is important to understand the mechanisms that regulate intracellular localization of Dab1. In addition to a binding pocket that recognizes the NPXY sequence motifs of the receptor tails, Dab1 PTB domain contains a lipid‐binding region that selectively recognizes phosphatidylinositide bisphosphate (PIP2). Here, we show PIP2 binding is required for membrane localizations of Dab1, and mutations within this binding region are detrimental to both Reelin‐independent basal phosphorylation and Reelin‐induced phosphorylation of Dab1. Our results suggest that other signaling pathways that alter PIP2 levels within the cell membrane may modulate Reelin signaling by regulating intracellular distribution of Dab1.