Modulation of integrin function in hematopoietic progenitor cells by CD43 engagement: possible involvement of protein tyrosine kinase and phospholipase C-gamma.
Attachment of cells to extracellular matrix components is critical for the regulation of hematopoiesis. CD43 is a mucin-like transmembrane sialoglycoprotein expressed on the surface of almost all hematopoietic cells. A highly extended structure of extracellular mucin with negative charge may function as a repulsive barrier to hematopoietic cells. However, some investigators have shown that CD43 has proadhesive properties, and engagement of CD43 has been reported to upregulate integrin-mediated cell adhesion in T cells. We found that cross-linking of CD43 with monoclonal antibodies (MoAbs) enhanced integrin alpha4beta1 (very late antigen [VLA]-4) and alpha5 beta1 (VLA-5)-dependent adhesion of human cord blood CD34(+) cells to fibronectin. CD34(+) CD38(hi), but not CD34(+)CD38(-/low) cells responded significantly to the stimulus, suggesting that committed, but not stem and more immature progenitors are sensitive to CD43-mediated activation of integrin. To elucidate the molecular mechanism leading to integrin activation, we used the growth factor-dependent cell line MO7e. Cross-linking of CD43 induced tyrosine phosphorylation of several intracellular molecules including the protein tyrosine kinase Syk, the proto-oncogene product Cbl, and phospholipase C (PLC)-gamma2 in MO7e cells. Moreover, protein tyrosine kinase inhibitor herbimycin A and PLC inhibitor U73122 both blocked CD43-induced enhancement of adhesion to fibronectin. These results indicate that signals mediated through CD43 may increase integrin affinity to fibronectin via a pathway dependent on protein tyrosine kinase and PLC-gamma activation in hematopoietic progenitors.
Anzai
N
N
Departments of Microbiology/Immunology, Medicine, and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Gotoh
A
A
Shibayama
H
H
Broxmeyer
H E
HE
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology; D018952:Antigens, CD34 / Q000502:physiology; D016227:Benzoquinones; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D005312:Fetal Blood; D005353:Fibronectins / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D047029:Lactams, Macrocyclic; D051917:Leukosialin; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D011760:Pyrrolidinones / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D017469:Receptors, Fibronectin / Q000276:immunology / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing / Q000276:immunology / Q000502:physiology*; D016029:Receptors, Very Late Antigen / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D012795:Sialoglycoproteins / Q000502:physiology*; D019089:Stem Cell Factor / Q000494:pharmacology; D000072377:Syk Kinase; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018952:Antigens, CD34; D016227:Benzoquinones; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D004963:Estrenes; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D047029:Lactams, Macrocyclic; D051917:Leukosialin; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011760:Pyrrolidinones; D011809:Quinones; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; D016029:Receptors, Very Late Antigen; D011994:Recombinant Proteins; C465014:SPN protein, human; D012795:Sialoglycoproteins; D019089:Stem Cell Factor; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D017828:Rifabutin; C020754:herbimycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; C067419:CBL protein, human