Janus kinase 2 is involved in stromal cell-derived factor-1alpha-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, is a highly efficacious chemoattractant for CD34(+) hematopoietic progenitor cells. However, the SDF-1/CXCR4 signaling pathways that regulate hematopoiesis are still not well defined. This study reports that SDF-1alpha can stimulate the tyrosine phosphorylation of Janus kinase 2 (JAK2) and other members of the JAK/signal transduction and activation of transcription (STAT) family, including JAK1, tyrosine kinase 2, STAT2, and STAT4 in the human progenitor cell line, CTS. SDF-1alpha stimulation of these cells also enhanced the association of JAK2 with phosphatidylinositol 3 (PI3)-kinase. This enhanced association was abolished by pretreatment of cells with AG490, a specific JAK2 inhibitor. Furthermore, pretreatment of CTS cells with AG490 significantly inhibited SDF-1alpha-induced PI3-kinase activity, and inhibition of JAK2 with AG490 ablated the SDF-1alpha-induced tyrosine phosphorylation of multiple focal adhesion proteins (including focal adhesion kinase, related adhesion focal tyrosine kinase, paxillin, CrkII, CrkL, and p130Cas). Chemotaxis assays showed that inhibition of JAK2 diminished SDF-1alpha-induced migration in both CTS cells and CD34(+) human bone marrow progenitor cells. Hence, these results suggest that JAK2 is required for CXCR4 receptor-mediated signaling that regulates cytoskeletal proteins and cell migration through PI3-kinase pathways in hematopoietic progenitor cells. (Blood. 2001;97:3342-3348)
Zhang
X F
XF
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 4 Blackfan Circle, Boston, MA 02115, USA.
Wang
J F
JF
Matczak
E
E
Proper
J A
JA
Groopman
J E
JE
D048868:Adaptor Proteins, Signal Transducing; D001854:Bone Marrow Cells / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D053614:Janus Kinase 2; D009687:Nuclear Proteins / Q000378:metabolism; D051419:Paxillin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D050795:STAT2 Transcription Factor; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; C515255:CXCL12 protein, human; D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D019000:Phosphotyrosine; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C496050:PTK2 protein, human