CXC Chemokine Ligand 12-Induced Focal Adhesion Kinase Activation and Segregation into Membrane Domains Is Modulated by Regulator of G Protein Signaling 1 in Pro-B Cells

Joint Program in Transfusion Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
The Journal of Immunology (Impact Factor: 4.92). 04/2005; 174(5):2582-90. DOI: 10.4049/jimmunol.174.5.2582
Source: PubMed


CXCL12-induced chemotaxis and adhesion to VCAM-1 decrease as B cells differentiate in the bone marrow. However, the mechanisms that regulate CXCL12/CXCR4-mediated signaling are poorly understood. We report that after CXCL12 stimulation of progenitor B cells, focal adhesion kinase (FAK) and PI3K are inducibly recruited to raft-associated membrane domains. After CXCL12 stimulation, phosphorylated FAK is also localized in membrane domains. The CXCL12/CXCR4-FAK pathway is membrane cholesterol dependent and impaired by metabolic inhibitors of G(i), Src family, and the GTPase-activating protein, regulator of G protein signaling 1 (RGS1). In the bone marrow, RGS1 mRNA expression is low in progenitor B cells and high in mature B cells, implying developmental regulation of CXCL12/CXCR4 signaling by RGS1. CXCL12-induced chemotaxis and adhesion are impaired when FAK recruitment and phosphorylation are inhibited by either membrane cholesterol depletion or overexpression of RGS1 in progenitor B cells. We conclude that the recruitment of signaling molecules to specific membrane domains plays an important role in CXCL12/CXCR4-induced cellular responses.

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Available from: Yi Le, Apr 06, 2015
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    • "The function of the CXCR4 receptor depends on its incorporation into membrane lipid domains called lipid rafts and several signals from other membrane receptors (e.g., G-protein-coupled C3a anaphylatoxin receptor—C3aR) or integrins that may increase the incorporation of CXCR4 into membrane lipid rafts, enhancing its signalling [35] [36]. Finally, CXCR4 is the subject of negative regulation by regulators of Gprotein signalling (RGS) proteins which may regulate CXCR4 signalling differently in different tissues [37] [38] "
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    Cardiology Research and Practice 02/2012; 2012(2):143209. DOI:10.1155/2012/143209
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    • "Rho A (50%), Ras H (95%) and c-Src (90%) are also detected in this fraction [24] [25]. In adherent pro-B cells, stimulation by CXL chemokine ligand 12 induces FAK-Y397 phosphorylation and recruitment of FAK and PI3K regulating subunit p85 into lipid membrane domains [26]. In endothelial cells, detachment also induced a rapid decrease in membrane order correlated with cholera toxin subunit B-stained domains internalization. "
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    • "signal transduction . Given that the membrane rafts play a crucial role in the activation of Akt ( Ha et al . 2003 ) , we have demonstrated that Akt neither resided in nor was recruited to the raft domains upon stimulation of FPRL - 1 . In pro - B cells , CXC chemo - kine promotes the translocation and subsequent stimulation of PI3K in the rafts ( Le et al . 2005 ) . This translocation of PI3K may partially explain how Akt can be activated while it is not raft - resided . Likewise , IKK was absent in the plasma membrane no matter whether U87 cells were stimulated with agonist or not ( Fig . 10 ) , suggesting that IKK receives signals from the plasma membrane through the cytosolic compartment . I"
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