The mosaic receptor sorLA/LR11 binds components of the plasminogen-activating system and platelet-derived growth factor-BB similarly to LRP1 (low-density lipoprotein receptor-related protein), but mediates slow internalization of bound ligand.
The type-1 receptor sorLA/LR11, a member of the Vps10p-domain receptor family that also contains domains characterizing members of the LDL (low-density lipoprotein) receptor family, has been shown to induce increased uPAR (urokinase receptor) expression as well as enhanced migration and invasion activities in smooth muscle cells in the presence of PDGF-BB (platelet-derived growth factor-BB). Here we show that sorLA interacts with both components of the plasminogen activating system and PDGF-BB similarly to LRP1 (LDL receptor-related protein/alpha2-macroglobulin receptor), which is an important clearance receptor with established functions in controlling uPAR expression as well as PDGF-BB signalling. In contrast with LRP1, sorLA does not interact with alpha2-macroglobulin, which is a binding protein for several growth factors, including PDGF-BB. By using LRP1-deficient cells transfected with sorLA, we demonstrate that sorLA-bound ligand is internalized at a much lower rate than LRP1-bound ligand, and that sorLA is inefficient in regulating cell surface uPAR expression, which depends on rapid internalization of the ternary complex between urokinase-type plasminogen activator, its type-1 inhibitor, and uPAR. Thus, although overlapping with regard to binding profiles, sorLA is substantially less efficient as a clearance receptor than LRP1. We propose that sorLA can divert ligands away from LRP1 and thereby inhibit both their clearance and signalling events mediated by LRP1.
Gliemann
Jørgen
J
Institute of Medical Biochemistry, University of Aarhus, Ole Worms Allé bldg 170, DK-8000 Arhus C, Denmark. jg@biokemi.au.dk
Hermey
Guido
G
Nykjaer
Anders
A
Petersen
Claus M
CM
Jacobsen
Christian
C
Andreasen
Peter A
PA
D000818:Animals; D000077214:Becaplermin; D016466:CHO Cells / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000172:deficiency; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000378:metabolism*; D011973:Receptors, LDL / Q000737:chemistry / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D014162:Transfection / Q000379:methods; D000511:alpha-Macroglobulins / Q000378:metabolism
D026563:LDL-Receptor Related Protein-Associated Protein; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D026901:Membrane Transport Proteins; C524898:PLAUR protein, human; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D055293:Receptors, Urokinase Plasminogen Activator; C102582:SORL1 protein, human; D000511:alpha-Macroglobulins; D000077214:Becaplermin