Cross-talk between α4β1/α5β1 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

Reuben Kapur, Ryan Cooper, Lei Zhang, David A. Williams

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72 Citations (Scopus)

Abstract

Erythroid progenitor cells (EPCs) are deficient in mice lacking either the ligand stem cell factor (SCF), its receptor c-Kit, or β1-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 α4β1 (FN-H296) or α5β1 (FN-CH271) or both α4β1 and α5β1 (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 n 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-XL, 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 α4β1 and α5β1 result in distinct biologic Outcomes, including death via α4β1 and survival/proliferation via α5β1.

Original languageEnglish
Pages (from-to)1975-1981
Number of pages7
JournalBlood
Volume97
Issue number7
DOIs
StatePublished - Apr 1 2001

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Focal Adhesion Protein-Tyrosine Kinases
Mitogen-Activated Protein Kinases
Cell Survival
Chemical activation
Cells
Erythroid Precursor Cells
Integrins
Growth
Adhesion
Proto-Oncogene Proteins c-kit
Receptor Protein-Tyrosine Kinases
Cell death
Fibronectins
Phosphotransferases
Binding Sites
Ligands
Ligation
Peptides
Cultured Cells
Molecules

ASJC Scopus subject areas

  • Hematology

Cite this

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title = "Cross-talk between α4β1/α5β1 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",
abstract = "Erythroid progenitor cells (EPCs) are deficient in mice lacking either the ligand stem cell factor (SCF), its receptor c-Kit, or β1-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 α4β1 (FN-H296) or α5β1 (FN-CH271) or both α4β1 and α5β1 (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 n 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-XL, 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 α4β1 and α5β1 result in distinct biologic Outcomes, including death via α4β1 and survival/proliferation via α5β1.",
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T1 - Cross-talk between α4β1/α5β1 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

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AU - Cooper, Ryan

AU - Zhang, Lei

AU - Williams, David A.

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N2 - Erythroid progenitor cells (EPCs) are deficient in mice lacking either the ligand stem cell factor (SCF), its receptor c-Kit, or β1-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 α4β1 (FN-H296) or α5β1 (FN-CH271) or both α4β1 and α5β1 (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 n 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-XL, 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 α4β1 and α5β1 result in distinct biologic Outcomes, including death via α4β1 and survival/proliferation via α5β1.

AB - Erythroid progenitor cells (EPCs) are deficient in mice lacking either the ligand stem cell factor (SCF), its receptor c-Kit, or β1-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 α4β1 (FN-H296) or α5β1 (FN-CH271) or both α4β1 and α5β1 (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 n 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-XL, 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 α4β1 and α5β1 result in distinct biologic Outcomes, including death via α4β1 and survival/proliferation via α5β1.

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