Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP). Evidence for integrated co-receptor function betwenn LRP and the PDGF.
The low density lipoprotein receptor-related protein (LRP) functions in the catabolism of numerous ligands including proteinases, proteinase inhibitor complexes, and lipoproteins. In the current study we provide evidence indicating an expanded role for LRP in modulating cellular signaling events. Our results show that platelet-derived growth factor (PDGF) BB induces a transient tyrosine phosphorylation of the LRP cytoplasmic domain in a process dependent on PDGF receptor activation and c-Src family kinase activity. Other growth factors, including basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor-1, were unable to mediate tyrosine phosphorylation of LRP. The basis for this selectivity may result from the ability of LRP to bind PDGFBB, because surface plasmon resonance experiments demonstrated that only PDGF, and not basic fibroblast growth factor, epidermal growth factor, or insulin-like growth factor-1, bound to purified LRP immobilized on a sensor chip. The use of LRP mini-receptor mutants as well as in vitro phosphorylation studies demonstrated that the tyrosine located within the second NPXY motif found in the LRP cytoplasmic domain is the primary site of tyrosine phosphorylation by Src and Src family kinases. Co-immunoprecipitation experiments revealed that PDGF-mediated tyrosine phosphorylation of LRPs cytoplasmic domain results in increased association of the adaptor protein Shc with LRP and that Shc recognizes the second NPXY motif within LRPs cytoplasmic domain. In the accompanying paper, Boucher et al. (Boucher, P., Liu, P. V., Gotthardt, M., Hiesberger, T., Anderson, R. G. W., and Herz, J. (2002) J. Biol. Chem. 275, 15507-15513) reveal that LRP is found in caveolae along with the PDGF receptor. Together, these studies suggest that LRP functions as a co-receptor that modulates signal transduction pathways initiated by the PDGF receptor.
Loukinova
Elena
E
Department of Vascular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
Ranganathan
Sripriya
S
Kuznetsov
Sergey
S
Gorlatova
Natalia
N
Migliorini
Mary M
MM
Loukinov
Dmitri
D
Ulery
Paula G
PG
Mikhailenko
Irina
I
Lawrence
Daniel A
DA
Strickland
Dudley K
DK
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000077214:Becaplermin; D001667:Binding, Competitive; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007700:Kinetics; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000493:pharmacokinetics / Q000494:pharmacology*; D021122:Protein Subunits; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011817:Rabbits; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020349:Surface Plasmon Resonance; D014162:Transfection; D019061:src-Family Kinases
D000911:Antibodies, Monoclonal; D000077214:Becaplermin; D000081247:CSK Tyrosine-Protein Kinase; D004815:Epidermal Growth Factor; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D026502:LDL-Receptor Related Proteins; D019869:Phosphatidylinositol 3-Kinases; D019000:Phosphotyrosine; D010982:Platelet-Derived Growth Factor; D021122:Protein Subunits; D011505:Protein-Tyrosine Kinases; D020574:Proto-Oncogene Proteins c-sis; D017479:Receptors, Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D019061:src-Family Kinases; C000631346:CSK protein, human