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Sequence Motifs in the Integrin ₄ Cytoplasmic Tail Required for Regulation of In Vivo Expansion of Murine Lymphoma Cells¹

Michaela Bittner^*, Uwe Gosslar^*, Arne Luz and Bernhard Holzmann^2,*,

^* Institute of Medical Microbiology, Immunology, and Hygiene, Technische Universität, Munich, Germany; Gesellschaft für Strahlung und Umweltforschung-Institut für Pathologie Neuherberg, Oberschleissheim, Germany; and Department of Surgery, Klinikum rechts der Isar, Technische Universität, Munich, Germany

The binding of integrins to cognate ligands is tightly controlled by intracellular signals. Conversely, integrin occupancy generates biochemical signals inside the cell. The present study examined whether concepts of integrin function established by in vitro analysis apply to regulation of receptor function in complex biologic settings in vivo using a mouse model of tumor metastasis. Integrin ₄ subunits were truncated at amino acid Gln¹⁰¹⁴ (A4-1014), preserving the conserved GFFKR motif, and at position Glu¹⁰²¹ (A4-1021). In vitro adhesion assays revealed that cytoplasmic tail truncations did not affect constitutive ligand binding of ₄ integrins, while agonist-induced adhesion was abolished by the A4-1014, but not by the A4-1021, mutation. Inducible ligand binding of ₄ integrins was dependent on cytoskeletal function, whereas constitutive adhesion was not. In vivo metastasis formation assays demonstrated that expansion of murine T lymphoma cells in spleen is strongly inhibited by the wild-type ₄ subunit and the A4-1021 mutant. In contrast, the in vivo phenotype of ₄ integrin expression in lymphoma cells was completely abrogated by the A4-1014 mutation. Cross-linking of ₄ integrins in vitro inhibited proliferation and induced apoptosis of LB cells expressing wild-type ₄ subunits or the A4-1021 mutant, but not of LB-A4-1014 cells. In summary, these results demonstrate that sequence motifs regulating cytoskeleton-dependent ₄ integrin activation in vitro are essential for the control of LB lymphoma cell expansion both in vitro and in vivo.

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