Article thumbnail

Phosphoprotein Associated with Glycosphingolipid-Enriched Microdomains Differentially Modulates Src Kinase Activity in Brain Maturation

By Sabine Lindquist, Diana Karitkina, Kristina Langnaese, Anita Posevitz-Fejfar, Burkhart Schraven, Ramnik Xavier, Brian Seed and Jonathan A. Lindquist

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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3167820
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2008). A displaced PAG enhances proximal signaling and SDF-1-induced T cell migration.
  2. (2007). A novel negative regulatory function of PAG: blocking Ras activation.
  3. (1989). A protein tyrosine kinase involved in regulation of pp60 c-src function.
  4. (2001). A unique role for Fyn in CNS myelination.
  5. (2008). Activation of cSrc and Fyn Kinases by Protein-tyrosine Phosphatase RPTPalpha Is Substratespecific and Compatible with Lipid Raft Localization.
  6. (2001). Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor.
  7. (1998). Brainspecific src oncogene mRNA mapped in rat brain by in situ hybridisation.
  8. (2005). C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) - endogenous negative regulators of Src-family protein kinases.
  9. (2005). Cbp deficiency alters Csk localization in lipid rafts but does not affect Tcell development.
  10. (1994). Combined deficiencies of Src, Fyn and Yes tyrosine kinases in mutant mice.
  11. (1993). Constitutive activation of Src family kinases in mice that lack Csk.
  12. (1997). Csk and BatK show opposite temporal expression in the rat CNS: consistent with its late expression in development, BatK induces differentiation of PC12 cells.
  13. (2006). Cskbinding protein mediates sequential enzymatic down-regulation and degradation of Lyn in Erythropoeitin-stimulated cells.
  14. (2002). Cutting Edge: Transmembrane phosphoprotein Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains as a negative feedback regulator of mast cell signaling through the FcepsilonRI.
  15. (2004). Depolarization-induced translocation of the RNA-binding protein Sam68 to the dendrites of hippocampal neurons.
  16. (1993). Disruption of the Csk gene, encoding a negative regulator of Src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice.
  17. (1995). Focal adhesion kinase in the brain: Novel subcellular localization and specific regulation by Fyn tyrosine kinase in mutant mice.
  18. (1997). Fyn-kinase as a determinant of ethanol sensitivity: relation to NMDA-receptor function.
  19. (2003). Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn.
  20. (1992). Impaired longterm potentiation, spatial learning, and hippocampal development in fyn mutant mice.
  21. (1995). In situ hybridization techniques to map processing enzymes,
  22. (1994). Increased fearfulness of Fyn tyrosine kinase deficient mice.
  23. (1994). Initial events of myelination involve Fyn tyrosine kinase signaling.
  24. (2008). Interactions between the Fyn SH3-domain and adaptor protein Cbp/PAG derived ligands, effects on kinase activity and affinity.
  25. (2009). Laminin alters fyn regulatory mechanisms and promotes oligodendrocyte development.
  26. (2003). LIME, a novel transmembrane adaptor protein, associates with p56lck and mediates T cell activation.
  27. (2003). LIME: a new membrane Raft-associated adaptor protein involved in CD4 and CD8 coreceptor signaling.
  28. (2004). Mechanism of Csk-mediated downregulation of Src family tyrosine kinases in epidermal growth factor signaling.
  29. (2004). Negative regulation of immunoglobulin E-dependent allergic responses by Lyn kinase.
  30. (2006). Negative regulation of protease-activated receptor 1-induced Src kinase activity by the association of phosphocaveolin-1 with Csk.
  31. (1998). Neuroendocrine protein 7B2 is essential for proteolytic conversion and activation of proprotein convertase 2 in vivo.
  32. (2008). Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts.
  33. (2007). Paxillin family members function as Csk binding proteins that regulate Lyn activity in human and murine platelets.
  34. (2000). Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation.
  35. (2003). Protein tyrosine phosphatase alpha (PTP alpha) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety.
  36. (2008). Proteomic identification of ZO1/2 as a novel scaffold for Src/Csk regulatory circuit.
  37. (2008). Regulation of FynT function by dual domain docking on PAG/Cbp.
  38. (2005). Role of Src family tyrosine kinases in the down-regulation of epidermal growth factor signaling in PC12 cells.
  39. (2004). SAP increases FynT kinase activity and is required for phosphorylation of SLAM and Ly9.
  40. (2003). Site-specific gene targeting in mouse embryonic stem cells withn intact bacterial artificial chromosomes.
  41. (1999). Src family kinases are required for integrin but not PDGFR signal transduction.
  42. (2004). Src family kinases, key regulators of signal transduction.
  43. (2005). Src kinase regulation by phosphorylation and dephosphorylation.
  44. (2005). Tarakhovsky A
  45. (1999). Targeted disruption of the tyrosine phosphatase PTPa leads to constitutive downregulation of the kinases Src and Fyn.
  46. (2008). The Cskbinding protein PAG regulates PDGF-induced Src mitogenic signaling via GM1.
  47. (2008). The Lipid Raft-Anchored Adaptor Protein Cbp Controls the Oncogenic Potential of c-Src.
  48. (1997). Translocation of the Csk homologous kinase (Chk/Hyl) controls activity of CD36-anchored Lyn tyrosine kinase in thrombin-stimulated platelets.
  49. (2003). Transmembrane adapters: attractants for cytoplasmic effectors.
  50. (2000). Transmembrane phosphoprotein Cbp positively regulates the activity of the carboxyl-terminal Src kinase,
  51. (2000). Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases.
  52. (2003). Transmembrane phosphoprotein Cbp senses cell adhesion signaling mediated by Src family kinase in lipid rafts.
  53. (2003). Veilette A
  54. (2007). Veillette A