Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells.
Hematopoietic stem/progenitor cells (HSC/P) reside in the bone marrow in distinct anatomic locations (niches) to receive growth, survival and differentiation signals. HSC/P localization and migration between niches depend on cell-cell and cell-matrix interactions, which result from the cooperation of cytokines, chemokines and adhesion molecules. The CXCL12-CXCR4 pathway, in particular, is essential for myelopoiesis and B lymphopoiesis but the molecular mechanisms of CXCL12 action remain unclear. We previously noted a strong correlation between prolonged CXCL12-mediated focal adhesion kinase (FAK) phosphorylation and sustained pro-adhesive responses in progenitor B cells, but not in mature B cells. Although FAK has been well studied in adherent fibroblasts, its function in hematopoietic cells is not defined. We used two independent approaches to reduce FAK expression in (human and mouse) progenitor cells. RNA interference (RNAi)-mediated FAK silencing abolished CXCL12-induced responses in human pro-B leukemia, REH cells. FAK-deficient REH cells also demonstrated reduced CXCL12-induced activation of the GTPase Rap1, suggesting the importance of FAK in CXCL12-mediated integrin activation. Moreover, in FAK(flox/flox) hematopoietic precursor cells, Cre-mediated FAK deletion resulted in impaired CXCL12-induced chemotaxis. These studies suggest that FAK may function as a key intermediary in signaling pathways controlling hematopoietic cell lodgment and lineage development.
Glodek
A M
AM
Department of Pathology, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA, USA.
Le
Y
Y
Dykxhoorn
D M
DM
Park
S-Y
SY
Mostoslavsky
G
G
Mulligan
R
R
Lieberman
J
J
Beggs
H E
HE
Honczarenko
M
M
Silberstein
L E
LE
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001402:B-Lymphocytes / Q000473:pathology*; D002448:Cell Adhesion; D002454:Cell Differentiation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis; D003114:Colony-Forming Units Assay; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D006413:Hematopoietic System; D006801:Humans; D019426:Integrases / Q000378:metabolism; D016086:Lentivirus; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D034622:RNA Interference; D019718:Receptors, CXCR4; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D000950:Antigens, Ly; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019718:Receptors, CXCR4; D019009:Proto-Oncogene Proteins c-kit; D051416:Focal Adhesion Protein-Tyrosine Kinases; C045073:Cre recombinase; D019426:Integrases; D020827:rap1 GTP-Binding Proteins