Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Forms a Signaling Complex with Platelet-derived Growth Factor Receptor-β in Endosomes and Regulates Activation of the MAPK Pathway

Abstract

In addition to its endocytic function, the low density lipoprotein receptor-related protein 1 (LRP1) also contributes to cell signaling events. In the current study, the potential of LRP1 to modulate the platelet-derived growth factor (PDGF) signaling pathway was investigated. PDGF is a key regulator of cell migration and proliferation and mediates the tyrosine phosphorylation of LRP1 within its cytoplasmic domain. In WI-38 fibroblasts, PDGF-mediated LRP1 tyrosine phosphorylation occurred at 37°C but not at 4°C, where endocytosis is minimized. Furthermore, blockade of endocytosis with the dynamin inhibitor, dynasore, also prevented PDGFmediated LRP1 tyrosine phosphorylation. Immunofluorescence studies revealed co-localization of LRP1 with the PDGF receptor after PDGF treatment within endosomal compartments, whereas surface biotinylation experiments confirmed that phosphorylated LRP1 primarily originates from intracellular compartments. Together, the data reveal the association of these two receptors in endosomal compartments where they form a signaling complex. To study the contribution of LRP1 to PDGF signaling, we used mouse embryonic fibroblasts genetically deficient in LRP1 and identified phenotypic changes in these cell lines in response to PDGF stimulation by performing phospho-site profiling. Of 38 phosphorylated proteins analyzed, 8 were significantly different in LRP1 deficient fibroblasts and were restored when LRP1 was expressed back in these cells. Importantly, the results revealed that LRP1 expression is necessary for PDGF-mediated activation of ERK. Overall, the studies reveal that LRP1 associates with the PDGF receptor in endosomal compartments and modulates its signaling properties affecting the MAPK and Akt/phosphatidylinositol 3-kinase pathways.

Antagonism and synergy between extracellular BMP modulators Tsg and BMPER to balance blood vessel formation

“…LRP1 is known to recognize more than 30 distinct ligands, cytoplasmic adaptor proteins and modulates the activity of other transmembrane receptors such as PDGFR-b or TGF-bR. Furthermore, LRP1 itself is known to activate Akt and Erk signalling pathways (Lillis et al, 2008;Muratoglu et al, 2010). Therefore, it is tempting to speculate that also BMP receptors, ligands and modulators form complexes with high signalling activity centres such as LRP1, which would localize the processing of incoming signals on the cell.…”

Molecular Biology of Atherosclerosis

“…LRP1 interaction with PDGFR␤ may occur in endosomes after internalization of the two receptors (1256,1296). Activated PDGFR␤ can tyrosine phosphorylate the cytoplasmic tail of LRP1 (possibly with assistance from Src and PI3K activity), followed by binding of ShcA, then Grb2-Sos, and ERK activation (1256,1296,1744). LRP1 also binds the ubiquitin ligase Cbl and may also modulate Cbl ubiquitination of PDGFR␤ and therefore its expression or degradation (1744).…”

Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

“…In Schwann cells, LRP1 activates PI3K/Akt-mediated cell survival signaling pathways and counteracts endoplasmic reticulum stress (11,12). LRP1 also interacts with other receptors, including integrins (13), platelet-derived growth factor receptors (14), and urokinase-type plasminogen activator receptor (15). As a result, LRP1 functions in a diversity of cellular activities, including cell signaling and metabolism, migration, and blood-brain barrier integrity (16,17).…”