Binding of tissue-type plasminogen activator to the glucose-regulated protein 78 (GRP78) modulates plasminogen activation and promotes human neuroblastoma cell proliferation in vitro.

Journal Article (Journal Article)

The 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 K(m) and an increase in the V(max) 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 (98)LIGRTWNDPSVQQDIKFL(115). 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.

Full Text

Duke Authors

Cited Authors

  • Gonzalez-Gronow, M; Gomez, CF; de Ridder, GG; Ray, R; Pizzo, SV

Published Date

  • September 5, 2014

Published In

Volume / Issue

  • 289 / 36

Start / End Page

  • 25166 - 25176

PubMed ID

  • 25059665

Pubmed Central ID

  • PMC4155680

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

Digital Object Identifier (DOI)

  • 10.1074/jbc.M114.589341


  • eng

Conference Location

  • United States