The Low Density Lipoprotein Receptor-related Protein/α2-Macroglobulin Receptor Is a Receptor for Connective Tissue Growth Factor

Abstract

Connective tissue growth factor (CTGF) expression is regulated by transforming growth factor-␤ (TGF-␤) and strong up-regulation occurs during wound healing; in situ hybridization data indicate that there are high levels of CTGF expression in fibrotic lesions. Recently the binding parameters of CTGF to both high and lower affinity cell surface binding components have been characterized. Affinity cross-linking and SDS-polyacrylamide gel electrophoresis analysis demonstrated the binding of CTGF to a cell surface protein with a mass of ϳ620 kDa. We report here the purification of this protein by affinity chromatography on CTGF coupled to Sepharose and sequence information obtained by mass spectroscopy. The binding protein was identified as the multiligand receptor, low density lipoprotein receptor-related protein/␣ 2 -macroglobulin receptor (LRP). The identification of LRP as a receptor for CTGF was validated by several studies: 1) binding competition with many ligands that bind to LRP, including receptor-associated protein; 2) immunoprecipitation of CTGF-receptor complex with LRP antibodies; and 3) cells that are genetically deficient for LRP were unable to bind CTGF. Last, CTGF is rapidly internalized and degraded and this process is LRP-dependent. In summary, our data indicate that LRP is a receptor for CTGF, and may play an important role in mediating CTGF biology.

Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non–Small Cell Lung Cancer Cells

“…Possibly, the growth arrest in these cells occurred by CTGF-inducing expression of p53 through E2F1 and ARF. CTGF is a secreted protein that can mediate its activity through binding to integrins (4), bone morphogenetic protein (41), and low-density lipoprotein receptor -related proteins (42,43). Conditioned medium from CTGF-transfected cells inhibited cell proliferation of the NSCLC NCI-H460 cells as well as the breast cancer MCF-7 cells; these latter cells have been shown to have enhanced apoptosis in the presence of recombinant CTGF (15).…”

Immunocytochemical Traits of Type IV Fibrocytes and Their Possible Relations to Cochlear Function and Pathology

“…It has been shown that the LRP1 binds CTGF (Segarini et al 2001). LRP1 appears to be the only CTGF receptor that has thus far been identified.…”

“…It may be that the observed loss of type IV fibrocytes contributed to the unusual loss of neural function through a lack of CTGF action upon the LRP1 receptors in the ganglion cells. LRP1 binds a variety of ligands, among which is CTGF (Segarini et al 2001;Gao and Brigstock 2003;Shi-Wen et al 2008). LRP1 has been reported to be associated with N-methyl-Daspartate receptors and PSD-95, both of which are present in spiral ganglion cells (Safieddine and Eybalin 1992;Kuriyama et al 1993;Davies et al 2001) and this association is believed to modulate synaptic transmission (May et al 2004).…”

Differential Regulation of Angiotensin II-induced Expression of Connective Tissue Growth Factor by Protein Kinase C Isoforms in the Myocardium

“…It has been suggested that CTGF is an essential mediator for the biological actions of TGF␤1 and bone morphogenetic protein (7), possibly via the modulation of the cytokine interaction with their cell surface receptors (7). Although a cell surface receptor mediating CTGF-induced biological responses has not been identified, tyrosine phosphorylation of low density lipoprotein receptor-related protein after its binding by CTGF with high affinity has been reported (8) and has been suggested to be associated with myofibroblast differentiation in the presence of TGF␤1 (9). Increased expression of CTGF has been reported in multiple fibrotic diseases such as renal (10) and lung (11) fibrosis.…”