SHP2 and cbl participate in alpha-chemokine receptor CXCR4-mediated signaling pathways.
Stromal cell-derived factor (SDF)-1alpha and its receptor, CXCR4, play an important role in cell migration, embryonic development, and human immunodeficiency virus infection. However, the cellular signaling pathways that mediate these processes are not fully elucidated. We and others have shown that the binding of SDF-1alpha to CXCR4 activates phosphatidylinositol-3 kinase (PI-3 kinase), p44/42 mitogen-associated protein kinase, and the transcription factor nuclear factor-kappaB, and it also enhances the tyrosine phosphorylation and association of proteins involved in the formation of focal adhesions. In this study, we examined the role of phosphatases in CXCR4-mediated signaling pathways. We observed significant inhibition of SDF-1alpha-induced migration by phosphatase inhibitors in CXCR4-transfected pre-B lymphoma L1.2 cells, Jurkat T cells, and peripheral blood lymphocytes. Further studies revealed that SDF-1alpha stimulation induced robust tyrosine phosphorylation in the SH2-containing phosphatase SHP2. SHP2 associated with the CXCR4 receptor and the signaling molecules SHIP, cbl, and fyn. Overexpression of wild-type SHP2 increased SDF-1alpha-induced chemotaxis. Enhanced activation of fyn and lyn kinases and the tyrosine phosphorylation of cbl were also observed. In addition, SDF-1alpha stimulation enhanced the association of cbl with PI-3 kinase, Crk-L, and 14-3-3beta proteins. Our results suggest that CXCR4-mediated signaling is regulated by SHP2 and cbl, which collectively participate in the formation of a multimeric signaling complex.
Chernock
R D
RD
Divisions of Experimental Medicine and Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Cherla
R P
RP
Ganju
R K
RK
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D046911:Macromolecular Substances; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D051076:Proto-Oncogene Proteins c-fyn; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases / Q000378:metabolism
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; C482982:YWHAB protein, human; D019000:Phosphotyrosine; D014446:Tyrosine 3-Monooxygenase; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; C067419:CBL protein, human