Chemotaxis--the guided movement of cells in chemical gradients--probably first emerged in our single-celled ancestors and even today is recognizably similar in neutrophils and amoebae. Chemotaxis enables immune cells to reach sites of infection, allows wounds to heal and is crucial for forming embryonic patterns. Furthermore, the manipulation of chemotaxis may help to alleviate disease states, including the metastasis of cancer cells. This review discusses recent results concerning how cells orientate in chemotactic gradients and the role of phosphatidylinositol-3,4,5-trisphosphate, what produces the force for projecting pseudopodia and a new role for the endocytic cycle in movement.
Summary
DSL ligands activate Notch by inducing cleavage and shedding of the receptor ectodomain—an event that requires ligand to be endocytosed in signal-sending cells by the adaptor protein Epsin. Two classes of explanation for this unusual requirement are: (i) recycling models, in which ligand must be endocytosed to be modified or repositioned before it binds Notch, and (ii) pulling models, in which ligand must be endocytosed after it binds Notch to exert force that exposes an otherwise buried cleavage site. We demonstrate in vivo that ligands that cannot enter the Epsin pathway nevertheless bind Notch but fail to activate the receptor because they cannot exert sufficient force. This argues against recycling models and in favor of pulling models. Our results also suggest that once ligand binds receptor, activation depends on a competition between Epsin-mediated ligand endocytosis, which induces cleavage, and transendocytosis of ligand by receptor, which aborts the incipient signal.
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