Beta 1 integrin- and proteoglycan-mediated stimulation of T lymphoma cell adhesion and mitogen-activated protein kinase signaling by thrombospondin-1 and thrombospondin-1 peptides.
Cell-cell and cell-matrix interactions play important regulatory roles in lymphocyte homeostasis. Thrombospondin-1 (TSP1) is a matricellular protein that differentially promotes the adhesion of resting and activated T cells. In this work, we show that adhesion of Jurkat T cells on substrates coated with TSP1 or TSP1-derived peptides is mediated by beta 1 integrins, CD47, and heparan sulfate proteoglycans. Interactions with TSP1 or TSP1 peptides stimulated CD3-induced Ras activation and tyrosine phosphorylation of several T cell proteins. The signals from TSP1 and its derived peptides differentially synergized with activation of the TCR to induce phosphorylation of linker for activation of T cells (LAT) and extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase, and p38 kinases. The phosphorylation of ERK in the presence of full-length TSP1 was transient and dependent on a beta 1 integrin receptor. Interestingly, peptides derived from the type 1 repeats of TSP1 and a CD47-binding peptide from the carboxyl-terminal domain of TSP1 also stimulated mitogen-activated protein (MAP) kinase phosphorylation. Moreover, the TSP1 heparin-binding peptide synergized with Ab-ligated TCR to transduce signals to the nucleus, detected by activation of AP-1- and Elk-dependent transcription. This TSP1 peptide-dependent activation of AP-1 was inhibited by both heparin and the MAP/ERK kinase inhibitor PD98059, providing a functional link between adhesion molecule interaction and nuclear transactivation events via the MAP kinase pathways. These findings have implications for the role of extracellular TSP1 and TSP1 fragments in the regulation of T cell function during hemostasis, wound repair, and other inflammatory responses.
Wilson
K E
KE
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Li
Z
Z
Kara
M
M
Gardner
K L
KL
Roberts
D D
DD
D000595:Amino Acid Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins; D019204:GTP-Binding Proteins / Q000502:physiology; D006025:Glycosaminoglycans / Q000502:physiology; D006493:Heparin / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011509:Proteoglycans / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013431:Sulfates / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D006025:Glycosaminoglycans; D019012:Integrin beta1; D010446:Peptide Fragments; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D013431:Sulfates; D019700:Thrombospondin 1; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D014443:Tyrosine; D006493:Heparin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D015689:Oncogene Protein p21(ras)