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.
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.
Le
Yi
Y
Joint Program in Transfusion Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Honczarenko
Marek
M
Glodek
Aleksandra M
AM
Ho
Daniel K
DK
Silberstein
Leslie E
LE
D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002464:Cell Migration Inhibition; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D003545:Cysteine / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D021962:Membrane Microdomains / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020710:RGS Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D011506:Proteins; D020710:RGS Proteins; C080831:RGS1 protein, human; D050717:Retinoblastoma-Like Protein p130; D019010:Vascular Cell Adhesion Molecule-1; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D003545:Cysteine