Molecular events in transmembrane signaling via E-selectin. SHP2 association, adaptor protein complex formation and ERK1/2 activation

• Published in: The Journal of biological chemistry Vol. 276; no. 51; pp. 48549 - 48553
• Main Authors: Hu, Y, Szente, B, Kiely, J M, Gimbrone, Jr, M A
• Format: Journal Article
• Language: English
• Published: United States 21.12.2001
• Subjects: adaptor proteins; Adaptor Proteins, Signal Transducing; Animals; Base Sequence; Catalytic Domain; COS Cells; DNA Primers; E-selectin; E-Selectin - chemistry; E-Selectin - metabolism; Enzyme Activation; ERK1 protein; ERK2 protein; GRB2 Adaptor Protein; Intracellular Signaling Peptides and Proteins; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Oncogene Protein p21(ras) - metabolism; Phosphorylation; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - chemistry; Protein Tyrosine Phosphatases - metabolism; Proteins - metabolism; SHP2 protein; Signal Transduction; Son of Sevenless Protein, Drosophila - metabolism; Tyrosine - metabolism
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M105513200

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.