Plasminogen structural domains exhibit different functions when associated with cell surface GRP78 or the voltage-dependent anion channel.
Both the voltage-dependent anion channel and the glucose-regulated protein 78 have been identified as plasminogen kringle 5 receptors on endothelial cells. In this study, we demonstrate that kringle 5 binds to a region localized in the N-terminal domain of the glucose-regulated protein 78, whereas microplasminogen does so through the C-terminal domain of the glucose-regulated protein 78. Both plasminogen fragments induce Ca(2+) signaling cascades; however, kringle 5 acts through voltage-dependent anion channel and microplasminogen does so via the glucose-regulated protein 78. Because trafficking of voltage-dependent anion channel to the cell surface is associated with heat shock proteins, we investigated a possible association between voltage-dependent anion channel and glucose-regulated protein 78 on the surface of 1-LN human prostate tumor cells. We demonstrate that these proteins co-localize, and changes in the expression of the glucoseregulated protein 78 affect the expression of voltage-dependent anion channel. To differentiate the functions of these receptor proteins, either when acting singly or as a complex, we employed human hexokinase I as a specific ligand for voltage-dependent anion channel, in addition to kringle 5. We show that kringle 5 inhibits 1-LN cell proliferation and promotes caspase-7 activity by a mechanism that requires binding to cell surface voltage-dependent anion channel and is inhibited by human hexokinase I.
Gonzalez-Gronow
Mario
M
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA. gonza002@mc.duke.edu
Kaczowka
Steven J
SJ
Payne
Sturgis
S
Wang
Fang
F
Gawdi
Govind
G
Pizzo
Salvatore V
SV
D020816:Amino Acid Motifs; D053179:Caspase 7 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010958:Plasminogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D011498:Protein Precursors; D034741:RNA, Small Interfering; D050994:Voltage-Dependent Anion Channels; D010958:Plasminogen; D050995:Voltage-Dependent Anion Channel 1; D053179:Caspase 7; D010100:Oxygen