Cross-talk between alpha(4)beta(1)/alpha(5)beta(1) and c-Kit results in opposing effect on growth and survival of hematopoietic cells via the activation of focal adhesion kinase, mitogen-activated protein kinase, and Akt signaling pathways.
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)
The Section of Pediatric Hematology/Oncology, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, Indiana 46202, USA.
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Kapur
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Cooper
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Williams
D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D020239:Receptor Cross-Talk / Q000502:physiology*; D017469:Receptors, Fibronectin / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases