Abstract
Erythroid progenitor cells (EPCs) are deficient in mice lacking either the ligand stem cell factor (SCF), its receptor c-Kit, or beta(1)-integrins. In nonhematopoietic cells, integrins and receptor tyrosine kinases can collaborate to modulate cellular functions, providing evidence for cross-talk between signals emerging from these cell surface molecules. Using specific recombinant fibronectin peptides that contain the binding site for the integrin alpha(4)beta(1) (FN-H296) or alpha(5)beta(1) (FN-CH271) or both alpha(4)beta(1) and alpha(5)beta(1) (FN-CH296), this study investigated the effect of adhesion alone, or in combination with activation of c-Kit, on functional and biochemical outcomes in an EPC line, G1E-ER2, and primary EPCs. G1E-ER2 cells and primary EPCs cultured on FN-CH271 in the presence of c-Kit activation led to a significant increase in proliferation in comparison with cells grown on FN-H296 or FN-CH296. G1E-ER2 cells cultured on FN-H296 or FN-CH296 resulted in significant cell death in comparison to cells grown on FN-CH271. Activation of c-Kit enhanced the survival of G1E-ER2 cells grown on FN-H296 or FN-CH296; however, the rescue was only partial. The reduced survival of G1E-ER2 cells on FN-H296 correlated with reduced activation of Akt and expression of Bcl-2 and Bcl-x(L), whereas increase in proliferation on FN-CH271 correlated with significantly enhanced and sustained activation of focal adhesion kinase (FAK) and extracellular-regulated kinase (ERK) pathways. These data demonstrate that adhesion-induced signals emanating from ligation of alpha(4)beta(1) and alpha(5)beta(1) result in distinct biologic outcomes, including death via alpha(4)beta(1) and survival/proliferation via alpha(5)beta(1). (Blood. 2001;97:1975-1981)
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Cell Adhesion / drug effects
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Cell Adhesion / physiology
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Cell Division / drug effects
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Cell Division / physiology
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Enzyme Activation
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Erythroid Precursor Cells / cytology*
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Erythroid Precursor Cells / drug effects
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Erythroid Precursor Cells / metabolism
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Erythropoiesis / drug effects
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Erythropoiesis / physiology*
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Fibronectins / metabolism
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Fibronectins / pharmacology*
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Integrin alpha4beta1
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Integrins / physiology*
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MAP Kinase Signaling System / physiology
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Mice
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Mice, Knockout
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Mice, Mutant Strains
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Mitogen-Activated Protein Kinase 1 / physiology*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / physiology*
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology
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Protein Serine-Threonine Kinases*
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Protein-Tyrosine Kinases / physiology*
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-kit / physiology*
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Receptor Cross-Talk / physiology*
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Receptors, Fibronectin / physiology*
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Receptors, Lymphocyte Homing / physiology*
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
Substances
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Fibronectins
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Integrin alpha4beta1
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Integrins
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Peptide Fragments
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Proto-Oncogene Proteins
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Receptors, Fibronectin
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Receptors, Lymphocyte Homing
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Recombinant Proteins
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-kit
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Ptk2 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases