beta(1) integrin- and proteoglycan-mediated stimulation of T lymphoma celladhesion and mitogen-activated protein kinase signaling by thrombospondin-1 and thrombospondin-1 peptides

Cell-cell and cell-matrix interactions play important regulatory roles in l ymphocyte homeostasis, Thrombospondin-1 (TSP1) is a matricellular protein t hat 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 Pas activation and tyrosine phosphorylation of sever al T cell proteins, The signals from TSP1 and its derived peptides differen tially synergized with activation of the TCR to induce phosphorylation of t inker for activation of T Cells (LAT) and extracellular signal-regulated ki nase (ERK) 1/2, c-Jun N-terminal kinase, and p38 kinases, The phosphorylati on of ERK in the presence of full-length TSP1 was transient and dependent o n a beta(1) integrin receptor. Interestingly, peptides derived from the typ e 1 repeats of TSP1 and a CD47-binding peptide from the carboxyl-terminal d omain of TSP1 also stimulated mitogen-activated protein (MAP) kinase phosph orylation, Moreover, the TSP1 heparin-binding peptide synergized with Ab-li gated 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 PD9 8059, 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 oth er inflammatory responses.