Stromal cell-derived factor-ice stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C

The stromal cell-derived factor-1 (SDF-1) is an alpha chemokine that binds to the CXCR4 receptor. Knock-out studies in mice demonstrate that this liga nd-receptor pair is essential in hematopoiesis. One function of SDF-1 appea rs to be the regulation of migration of hematopoietic progenitor cells. We previously characterized signal transduction pathways induced by SDF-1 alph a in human hematopoietic progenitors and found tyrosine phosphorylation of focal adhesion components, including the related adhesion focal tyrosine ki nase (RAFTK), the adaptor molecule p130 Cas, and the cytoskeletal protein p axillin. To better understand the functional role of signaling molecules co nnecting the CXCR4 receptor to the process of hematopoietic migration, we s tudied SDF-1 alpha-mediated pathways in a model hematopoietic progenitor ce ll line (CTS), as well as in primary human bone marrow CD34(+) cells. We ob served that several other focal adhesion components, including focal adhesi on kinase (FAK) and the adaptor molecules Crk and Crk-L, are phosphorylated on SDF-1 alpha stimulation. Using a series of specific small molecule inhi bitors, both protein kinase C (PKC) and phosphoinositide-3 kinase (PI-3K) a ppeared to be required for SDF-1 alpha-mediated phosphorylation of focal ad hesion proteins and the migration of both CTS and primary marrow CD34(+) ce lls, whereas the mitogen-activated protein kinases ERK-1 and -2 were not. T hese studies further delineate the molecular pathways mediating hematopoiet ic progenitor migration and response to an essential chemokine, SDF-1 alpha . (Blood, 2000;95:2505-2513) (C) 2000 by The American Society of Hematology .