Janus kinase 2 is involved in stromal cell-derived factor-1 alpha-induced tyrosine phosphorylation of focal adhesion proteins and migration of hematopoietic progenitor cells

Stromal cell-derived factor-1 (SDF-1), the ligand for the CXCR4 receptor, i s a highly efficacious chemoattractant for CD34(+) hematopoietic progenitor cells. However, the SDF-1/CXCR4 signaling pathways that regulate hematopoi esis are still not well defined. This study reports that SDF-l alpha can st imulate the tyrosine phosphorylation of Janus kinase 2 (JAK2) and other mem bers of the JAK/signal transduction and activation of transcription (STAT) family, including JAK1, tyrosine kinase 2, STAT2, and STAT4 in the human pr ogenitor cell line, CTS. SDF-1 alpha stimulation of these cells also enhanc ed the association of JAK2 with phosphatidylinositol 3 (Pl3)kinase. This en hanced association was abolished by pretreatment of cells with AG490, a spe cific JAK2 inhibitor Furthermore, pretreatment of CTS cells with AG490 sign ificantly inhibited SDF-1 alpha -induced Pl3-kinase activity, and inhibitio n of JAK2 with AG490 ablated the SDF-1 alpha -induced tyrosine phosphorylat ion of multiple focal adhesion proteins (including focal adhesion kinase, r elated adhesion focal tyrosine kinase, paxillin, CrkII, CrkL, and p130Cas). Chemotaxis assays showed that inhibition of JAK2 diminished SDF-1 alpha -i nduced migration in both CTS cells and CD34(+) human bone marrow progenitor cells. Hence, these results suggest that JAK2 is required for CXCR4 recept or-mediated signaling that regulates cytoskeletal proteins and cell migrati on through Pl3-kinase pathways in hematopoietic progenitor cells. (Blood. 2 001;97:3342-3348) (C) 2001 by The American Society of Hematology.