Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibodies, Monoclonal / pharmacology
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Antigens, CD / physiology
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Antigens, CD34 / physiology
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Benzoquinones
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Cell Adhesion / drug effects
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Cell Adhesion / physiology*
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Cell Line
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Cross-Linking Reagents
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Enzyme Inhibitors / pharmacology
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Enzyme Precursors / metabolism
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Estrenes / pharmacology
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Fetal Blood
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Fibronectins / physiology
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / immunology
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Hematopoietic Stem Cells / physiology*
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Humans
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Integrin alpha4beta1
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Integrins / immunology
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Integrins / physiology*
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Intracellular Signaling Peptides and Proteins
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism*
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Kinetics
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Lactams, Macrocyclic
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Leukosialin
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Phospholipase C gamma
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Phosphorylation
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-cbl
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Pyrrolidinones / pharmacology
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Quinones / pharmacology
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Receptors, Fibronectin / immunology
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Receptors, Fibronectin / physiology*
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Receptors, Lymphocyte Homing / immunology
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Receptors, Lymphocyte Homing / physiology*
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Receptors, Very Late Antigen / physiology
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Recombinant Proteins / pharmacology
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Rifabutin / analogs & derivatives
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Sialoglycoproteins / physiology*
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Stem Cell Factor / pharmacology
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Syk Kinase
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Type C Phospholipases / antagonists & inhibitors
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Type C Phospholipases / metabolism*
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Ubiquitin-Protein Ligases*
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, CD34
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Benzoquinones
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Cross-Linking Reagents
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Enzyme Inhibitors
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Enzyme Precursors
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Estrenes
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Fibronectins
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Integrin alpha4beta1
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Integrins
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Lactams, Macrocyclic
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Leukosialin
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MAS1 protein, human
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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Pyrrolidinones
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Quinones
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Receptors, Fibronectin
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Receptors, Lymphocyte Homing
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Receptors, Very Late Antigen
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Recombinant Proteins
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SPN protein, human
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Sialoglycoproteins
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Stem Cell Factor
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1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
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Rifabutin
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herbimycin
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Granulocyte-Macrophage Colony-Stimulating Factor
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Type C Phospholipases
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Phospholipase C gamma
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CBL protein, human