Mannose 6-phosphate/insulin-like growth factor-II receptor targets the urokinase receptor to lysosomes via a novel binding interaction.
The urokinase-type plasminogen activator receptor (uPAR) plays an important role on the cell surface in mediating extracellular degradative processes and formation of active TGF-beta, and in nonproteolytic events such as cell adhesion, migration, and transmembrane signaling. We have searched for mechanisms that determine the cellular location of uPAR and may participate in its disposal. When using purified receptor preparations, we find that uPAR binds to the cation-independent, mannose 6-phosphate/insulin-like growth factor-II (IGF-II) receptor (CIMPR) with an affinity in the low micromolar range, but not to the 46-kD, cation-dependent, mannose 6-phosphate receptor (CDMPR). The binding is not perturbed by uPA and appears to involve domains DII + DIII of the uPAR protein moiety, but not the glycosylphosphatidylinositol anchor. The binding occurs at site(s) on the CIMPR different from those engaged in binding of mannose 6-phosphate epitopes or IGF-II. To evaluate the significance of the binding, immunofluorescence and immunoelectron microscopy studies were performed in transfected cells, and the results show that wild-type CIMPR, but not CIMPR lacking an intact sorting signal, modulates the subcellular distribution of uPAR and is capable of directing it to lysosomes. We conclude that a site within CIMPR, distinct from its previously known ligand binding sites, binds uPAR and modulates its subcellular distribution.
Nykjaer
A
A
Department of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus, Denmark. an@biokemi.aau.dk
Christensen
E I
EI
Vorum
H
H
Hager
H
H
Petersen
C M
CM
Røigaard
H
H
Min
H Y
HY
Vilhardt
F
F
Møller
L B
LB
Kornfeld
S
S
Gliemann
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism*; D008360:Mannosephosphates / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010960:Plasminogen Activators / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured
D008024:Ligands; D008360:Mannosephosphates; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C027693:mannose-6-phosphate; D010960:Plasminogen Activators