Interaction of the leucine-rich repeats of polycystin-1 with extracellular matrix proteins: possible role in cell proliferation.
Polycystin-1, the product of the PKD1 gene, is a membrane-bound multidomain protein with a unique structure and a molecular weight of approximately 460 kD. The purpose of this study is to investigate the binding of the cystein-flanked leucine-rich repeats (LRR) of polycystin-1 to extracellular matrix (ECM) components. These interactions may play a role in normal renal development as well as the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD). In vitro assays were used to assess the binding of a fusion protein containing the LRR of polycystin-1 and that of affinity purified polycystin-1 to a number of ECM components. The results showed that the LRR modulate the binding of polycystin-1 to collagen I, fibronectin, laminin, and cyst fluid-derived laminin fragments. The addition of the LRR fusion protein to cells in culture resulted in a significant dose-dependent reduction in the rate of proliferation. Cyst fluid-derived laminin fragments had a stimulatory effect on cell proliferation, which was reversed by the LRR fusion protein. These results suggest that the LRR of polycystin-1 act as mediators of the polycystin-1 interaction with the ECM. The observed suppression effect of the LRR on cell proliferation suggests a functional role of the LRR-mediated polycystin-1 involvement in cell-matrix and cell-cell interactions. These interactions may result in the enhanced cell proliferation that is a characteristic feature of ADPKD.
Malhas
Ashraf N
AN
Division of Life Sciences, King's College London, London, United Kingdom.
Abuknesha
Ramadan A
RA
Division of Life Sciences, King's College London, London, United Kingdom.
Price
Robert G
RG
Division of Life Sciences, King's College London, London, United Kingdom.
D000595:Amino Acid Sequence / Q000235:genetics; D002455:Cell Division / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007930:Leucine; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D020543:Proteome / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid / Q000502:physiology*; D016415:Sequence Alignment; D050396:TRPP Cation Channels; D014407:Tumor Cells, Cultured
D016326:Extracellular Matrix Proteins; D005982:Glutathione Transferase; D007930:Leucine; D011506:Proteins; D020543:Proteome; D011993:Recombinant Fusion Proteins; D050396:TRPP Cation Channels