Integrin inhibition through Lyn-dependent cross talk from CXCR4 chemokine receptors in normal human CD34+ marrow cells.
We studied the effects of Lyn ablation on CXCR4 receptor-mediated migration and adhesion of hematopoietic precursors. Down-regulation of Lyn expression with siRNA greatly reduced CXCR4-dependent hematopoietic cell movement, and increased cell adherence to stroma. This increase was associated with the up-regulated expression of activation-dependent epitopes of the beta(2) integrin LFA-1 and was prevented by antibodies that selectively block cell adhesion mediated by ICAM-1. Attachment to surfaces coated with ICAM-1 was also enhanced in Lyn-depleted hematopoietic cells, as compared with Lyn-expressing cells. Functional rescue experiments with Lyn siRNA targeting the 3' UTR indicated that the observed effects can be attributed directly to specific inhibition of Lyn. Our results show that in chemokine-stimulated hematopoietic cells Lyn kinase is a positive regulator of cell movement while negatively regulating adhesion to stromal cells by inhibiting the ICAM-1-binding activity of beta(2) integrins. These results provide a molecular mechanism for cross talk between the chemokine receptor CXCR4 and beta(2) integrins. This cross talk may allow chemokine receptors to modulate the arrest of rolling hematopoietic precursors on the surface of bone marrow stromal cells.
Nakata
Yuji
Y
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Tomkowicz
Brian
B
Gewirtz
Alan M
AM
Ptasznik
Andrzej
A
D018952:Antigens, CD34; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D018821:CD18 Antigens; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020239:Receptor Cross-Talk; D019718:Receptors, CXCR4 / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology; D019061:src-Family Kinases / Q000378:metabolism*
D018952:Antigens, CD34; D018821:CD18 Antigens; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D018799:Intercellular Adhesion Molecule-1; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases