1. Phosphoprotein Associated with Glycosphingolipid-Enriched Microdomains Differentially Modulates Src Kinase Activity in Brain Maturation
- Author
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Kristina Langnaese, Anita Posevitz-Fejfar, Ramnik J. Xavier, Diana Karitkina, Brian Seed, Sabine Lindquist, Jonathan A. Lindquist, and Burkhart Schraven
- Subjects
Mouse ,lcsh:Medicine ,Signal transduction ,Biochemistry ,Neurological Signaling ,Mice ,chemistry.chemical_compound ,Molecular cell biology ,0302 clinical medicine ,Signaling in Cellular Processes ,lcsh:Science ,In Situ Hybridization ,Protein kinase signaling cascade ,Mice, Knockout ,Neurons ,0303 health sciences ,Multidisciplinary ,Tyrosine-protein kinase CSK ,TCR signaling cascade ,Reverse Transcriptase Polymerase Chain Reaction ,Kinase ,Mechanisms of Signal Transduction ,Brain ,Signaling cascades ,Animal Models ,Signaling in Selected Disciplines ,Feeback Regulation ,src-Family Kinases ,Intercellular Signaling Peptides and Proteins ,Phosphorylation ,Cellular Types ,Transmembrane Signaling ,Tyrosine kinase signaling cascade ,Research Article ,Proto-oncogene tyrosine-protein kinase Src ,Blotting, Western ,Biology ,Immunological Signaling ,Protein Chemistry ,Signaling Pathways ,Glycosphingolipids ,03 medical and health sciences ,Model Organisms ,FYN ,Developmental Neuroscience ,Animals ,Immunoprecipitation ,Kinase activity ,Protein Interactions ,030304 developmental biology ,lcsh:R ,Membrane Proteins ,Proteins ,Tyrosine phosphorylation ,Signal Termination ,Phosphoproteins ,Molecular biology ,Regulatory Proteins ,Transmembrane Proteins ,Animals, Newborn ,chemistry ,nervous system ,Cellular Neuroscience ,Phosphoprotein ,lcsh:Q ,Molecular Neuroscience ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Src family kinases (SFK) control multiple processes during brain development and function. We show here that the phosphoprotein associated with glycosphigolipid-enriched microdomains (PAG)/Csk binding protein (Cbp) modulates SFK activity in the brain. The timing and localization of PAG expression overlap with Fyn and Src, both of which we find associated to PAG. We demonstrate in newborn (P1) mice that PAG negatively regulates Src family kinases (SFK). P1 Pag1(-/-) mouse brains show decreased recruitment of Csk into lipid rafts, reduced phosphorylation of the inhibitory tyrosines within SFKs, and an increase in SFK activity of >/ = 50%. While in brain of P1 mice, PAG and Csk are highly and ubiquitously expressed, little Csk is found in adult brain suggesting altered modes of SFK regulation. In adult brain Pag1-deficiency has no effect upon Csk-distribution or inhibitory tyrosine phosphorylation, but kinase activity is now reduced (-20-30%), pointing to the development of a compensatory mechanism that may involve PSD93. The distribution of the Csk-homologous kinase CHK is not altered. Importantly, since the activities of Fyn and Src are decreased in adult Pag1(-/-) mice, thus presenting the reversed phenotype of P1, this provides the first in vivo evidence for a Csk-independent positive regulatory function for PAG in the brain.
- Published
- 2011
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