title: GPI-anchored uPAR requires Endo180 for rapid directional sensing during chemotaxis.
abstract: Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in cell guidance and chemotaxis during normal and pathological events. uPAR is GPI-anchored and the mechanism by which it transmits intracellular polarity cues across the plasma membrane during directional sensing has not been elucidated. The constitutively recycling endocytic receptor Endo180 forms a trimolecular complex with uPAR in the presence of uPA, hence its alternate name uPAR-associated protein. Here, we demonstrate that Endo180 is a general promoter of random cell migration and has a more specific function in cell chemotaxis up a uPA gradient. Endo180 expression was demonstrated to enhance uPA-mediated filopodia production and promote rapid activation of Cdc42 and Rac. Expression of a noninternalizing Endo180 mutant revealed that promotion of random cell migration requires receptor endocytosis, whereas the chemotactic response to uPA does not. From these studies, we conclude that Endo180 is a crucial link between uPA-uPAR and setting of the internal cellular compass.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Sturge
authors.forename: Dirk
authors.initials: D
authors.lastname: Wienke
authors.forename: Lucy
authors.initials: L
authors.lastname: East
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Jones
authors.forename: Clare M
authors.initials: CM
authors.lastname: Isacke
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000502:physiology*; D004789:Enzyme Activation; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011554:Pseudopodia / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: C408294:Endo180; D017261:Glycosylphosphatidylinositols; D008562:Membrane Glycoproteins; C524898:PLAUR protein, human; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D011975:Receptors, Mitogen; D055293:Receptors, Urokinase Plasminogen Activator; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins