Abstract

he glucose-regulated protein 78 (GRP78) is a plasminogen (Pg) receptor on the cell surface. In this study, we demonstrate that GRP78 also binds the tissue-type plasminogen activator (t-PA), which results in a decrease in Km and an increase in the Vmax for both its amidolytic activity and activation of its substrate, Pg. This results in accelerated Pg activation when GRP78, t-PA, and Pg are bound together. The increase in t-PA activity is the result of a mechanism involving a t-PA lysine-dependent binding site in the GRP78 amino acid sequence 98LIGRTWNDPSVQQDIKFL115. We found that GRP78 is expressed on the surface of neuroblastoma SK-N-SH cells where it is co-localized with the voltage-dependent anion channel (VDAC), which is also a t-PA-binding protein in these cells. We demonstrate that both Pg and t-PA serve as a bridge between GRP78 and VDAC bringing them together to facilitate Pg activation. t-PA induces SK-N-SH cell proliferation via binding to GRP78 on the cell surface. Furthermore, Pg binding to the COOH-terminal region of GRP78 stimulates cell proliferation via its microplasminogen domain. This study confirms previous findings from our laboratory showing that GRP78 acts as a growth factor-like receptor and that its association with t-PA, Pg, and VDAC on the cell surface may be part of a system controlling cell growth. Binding of Tissue-Type Plasminogen Activator to the Glucose-Regulated Protein 78 (GRP78)Modulates Plasminogen Activation and Promotes Human Neuroblastoma Cell Proliferation in vitro. (PDF Download Available). Available from: https://www.researchgate.net/publication/264291548_Binding_of_Tissue-Type_Plasminogen_Activator_to_the_Glucose-Regulated_Protein_78_GRP78Modulates_Plasminogen_Activation_and_Promotes_Human_Neuroblastoma_Cell_Proliferation_in_vitro [accessed Apr 26, 2017].