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Stem Cells

Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells

Leukemia volume 21, pages 1723–1732 (2007)Cite this article

Abstract

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 FAKflox/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.

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Acknowledgements

This work was supported by NIH Grants 5 U24 HL074355-03 and 2 T32 HL 066987-06. We thank Dr John Manis for helpful advice and discussion.

Author information

Author notes

  1. A M Glodek

    Present address: 6Current address: Beth Israel Deaconess Medical Center, Boston, MA, USA.,

  2. M Honczarenko

    Present address: 7Current address: Biogen Idec, Cambridge, MA, USA.,

  3. A M Glodek and Y Le: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Pathology, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA, USA

    A M Glodek, Y Le, S-Y Park, M Honczarenko & L E Silberstein

  2. Harvard Medical School, Boston, MA, USA

    A M Glodek, Y Le, D M Dykxhoorn, S-Y Park, G Mostoslavsky, R Mulligan, J Lieberman, M Honczarenko & L E Silberstein

  3. Department of Pediatrics, CBR Center for Biomedical Research, Boston, MA, USA

    D M Dykxhoorn & J Lieberman

  4. Division of Molecular Medicine, Department of Genetics, Children's Hospital Boston, Boston, MA, USA

    G Mostoslavsky & R Mulligan

  5. Department of Ophthalmology and Physiology, University of California San Francisco, San Francisco, CA, USA

    H E Beggs

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Correspondence to L E Silberstein.

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Glodek, A., Le, Y., Dykxhoorn, D. et al. Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells. Leukemia 21, 1723–1732 (2007). https://doi.org/10.1038/sj.leu.2404769

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