Molecular events in transmembrane signaling via E-selectin. SHP2 association, adaptor protein complex formation and ERK1/2 activation.
E-selectin is a cytokine-inducible adhesion molecule that is expressed by activated endothelial cells at sites of inflammation. In addition to supporting rolling and stable arrest of leukocytes, there is increasing evidence that E-selectin functions in transmembrane signaling into endothelial cells during these adhesive interactions. We have previously shown that adhesion ... of HL-60 cells (which express ligands for E-selectin), or antibody-mediated cross-linking of E-selectin, results in formation of a Ras/Raf-1/phospho-MEK macrocomplex, extracellular signal-regulated protein kinase (ERK1/2) activation, and c-fos up-regulation. All of these downstream signaling events appear to require an intact cytoplasmic domain of E-selectin. Here we demonstrate that tyrosine 603 in the cytoplasmic domain of E-selectin is required for the E-selectin-dependent ERK1/2 activation. Tyrosine 603 plays an important role in mediating the association of E-selectin with SHP2, and the catalytic domain of SHP2 is, in turn, critical for E-selectin-dependent ERK1/2 activation. An adapter protein complex consisting of Shc.Grb2.Sos bridges between SHP2 and the Ras.Raf.phospho-MEK macrocomplex. These molecular events thus outline a mechanism by which cross-linking of E-selectin by engagement of ligands on adherent leukocytes can initiate a multifunctional signaling pathway in the activated endothelial cell at sites of inflammation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Base Sequence, COS Cells, Catalytic Domain, DNA Primers, E-Selectin, Enzyme Activation, GRB2 Adaptor Protein, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Oncogene Protein p21(ras), Phosphorylation, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proteins, Signal Transduction, Son of Sevenless Protein, Drosophila, Tyrosine
Adaptor Proteins, Signal Transducing, Animals, Base Sequence, COS Cells, Catalytic Domain, DNA Primers, E-Selectin, Enzyme Activation, GRB2 Adaptor Protein, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Oncogene Protein p21(ras), Phosphorylation, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proteins, Signal Transduction, Son of Sevenless Protein, Drosophila, Tyrosine
J. Biol. Chem.
Date: Dec. 21, 2001
PubMed ID: 11602579
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