Platelet-derived Growth Factor (PDGF)-induced Tyrosine Phosphorylation of the Low Density Lipoprotein Receptor-related Protein (LRP)

Abstract

The low density lipoprotein receptor-related protein (LRP) 1 is a large endocytic receptor containing a 515-kDa heavy chain to which ligands bind and a non-covalently associated 85-kDa light chain containing a transmembrane and cytoplasmic domain (for review see Ref. 1). LRP is one of 12 or more receptors that make up the LDL receptor superfamily and is essential for embryonic development in mice (2). A remarkable feature of LRP is its ability to bind and mediate the internalization of a diverse array of ligands, including proteinases (3, 4), proteinase-inhibitor complexes (5, 6), and lipoproteins (7). After binding to the LRP, the ligands are transported into endosomes where they uncouple in the reduced pH environment and are sorted to lysosomes for degradation. LRP recycles back to the cell surface where it is once again available to bind ligands.Recent studies indicate that in addition to their cargo transport function, certain LDL receptor family members also participate in signaling pathways. For example, the very low density lipoprotein receptor and apoE receptor 2 both participate in a signal transduction pathways mediated by reelin (8 -10). Reelin is secreted by Cajal-Retzius cell in the outermost layer of the cerebral cortex and controls the final position of neurons that migrate from the ventricular zone. Binding of reelin to either the very low density lipoprotein receptor or apoE receptor 2 induces tyrosine phosphorylation of disabled-1 (Dab1) (9, 10), an adaptor protein that interacts with the cytoplasmic domains of LDL receptor family members (11, 12) and functions in tyrosine kinase signaling pathways.In the case of LRP, accumulating evidence suggests a prominent but undefined role for this receptor in regulating cell physiology by facilitating signal transduction pathways. For example, LRP has been implicated as a component of the receptor complex for midkine (13), a heparin binding growth factor with migration-promoting and survival-promoting activities. Another LRP ligand, tissue type plasminogen activator, promotes late phase long term potentiation (14), and this activity appears to require its association with LRP (15). Finally, the binding of activated ␣ 2 M (␣ 2 M*) to LRP mediates calcium influx in neurons in a process that also involves N-methyl-D-

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

“…We then investigated pro-cath-D internalization by LRP1 using MEF that lacked M6P receptors ( Figure 1B Pro-cath-D and ectopic cath-D do not modulate LRP1b-chain tyrosine phosphorylation in fibroblasts The LRP1 at the plasma membrane is located in clathrin-coated pits and lipid rafts (Boucher et al, 2002;Zhang et al, 2004;Wu and Gonias, 2005), and it has been suggested that there are LRP1-induced signal transduction pathways triggered by tyrosine phosphorylation or RIP in lipid rafts (Boucher et al, 2002; von Cathepsin D, endocytosis and LRP1 RIP D Derocq et al Arnim et al, 2005;Wu and Gonias, 2005). We observed that LRP1b overproduction directs pro-cath-D to the lipid rafts (Beaujouin et al, 2010), suggesting that cath-D modulates the tyrosine phosphorylation of LRP1, as shown for the PDGF-BB (Boucher et al, 2002;Loukinova et al, 2002;Boucher and Gotthardt, 2004;Newton et al, 2005) and CTGF (Yang et al, 2004) growth factors, the tPA serine protease (Hu et al, 2006) and in fibroblasts transformed with v-Src (Barnes et al, 2001(Barnes et al, , 2003. We next investigated the effect of pro-cath-D on the tyrosine phosphorylation of LRP1b in fibroblasts.…”

“…It delivers most, but not all, of these ligands to lysosomes for degradation (Herz and Strickland, 2001;Gonias et al, 2004;Emonard et al, 2005;May et al, 2007). It has also been shown that LRP1 is involved in signal transduction by phosphorylation of the tyrosine in the cytoplasmic NPXY motifs of its b-chain and modulation of signaling pathways such as the MAP kinase pathway (Barnes et al, 2001(Barnes et al, , 2003Boucher et al, 2002;Boucher and Gotthardt, 2004;Loukinova et al, 2002;Yang et al, 2004;Newton et al, 2005;Hu et al, 2006). More recent studies have shown that LRP1 influences gene transcription by regulated intramembrane proteolysis (RIP) of its b-chain (May et al, 2002;Kinoshita et al, 2003;von Arnim et al, 2005;Zurhove et al, 2008).…”

Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

“…Our proposed scheme for a partial signaling pathway that enables TSPs to counteract the stimulatory effects of VEGF on cell cycle progression (Figure 10) is based in part on recent studies showing that platelet-derived growth factor (PDGF) binds and activates LRP1, an activity that results in a transient phosphorylation of tyrosine 63 in the second NPXY sequence of the LRP1 cytoplasmic domain (Boucher et al, 2002;Loukinova et al, 2002). This phosphorylation is mediated by Src or Src family members and requires the kinase domain of the PDGF ␤ receptor (Newton et al, 2005).…”

“…However, the bridging of LRP and the PDGF receptor by a common ligand, PDGF, is apparently not necessary for the phosphorylation of LRP (Newton et al, 2005). PDGF-induced phosphorylation of LRP also produces a docking site for Shc, a group of three homologous adapter proteins that contain a carboxy-terminal Src-homology 2 (SH2), and an amino-terminal PTB domain that is involved in signal transduction by protein tyrosine kinases (Loukinova et al, 2002). Specifically, Shc has been reported to couple activated growth factor receptors to signaling pathways that regulate the proliferation of mammalian cells and plays a role in activation of MAPK (Pelicci et al,1992;Ravichandran, 2001).…”

“…Binding of TSP1 and 2 to purified mouse VLDLR was measured with a BIA 3000 optical biosensor (Biacore AB, Uppsala, Sweden) as described previously (Loukinova et al, 2002). For these studies, the BIAcore sensor chip (type CM5; Biacore) was activated with a 1:1 mixture of 0.2 M N-ethyl-NЈ-(3-dimethylaminopropyl) carbodi-imide and 0.05 M N-hydroxysuccinimide in water.…”