Mechanism of thrombin clearance by human astrocytoma cells.
Enviado por Abel Baerga-Ortiz el
Título | Mechanism of thrombin clearance by human astrocytoma cells. |
Publication Type | Journal Article |
Year of Publication | 1999 |
Autores | Mentz, S, de Lacalle, S, Baerga-Ortiz, A, Knauer, MF, Knauer, DJ, Komives, EA |
Journal | J Neurochem |
Volume | 72 |
Issue | 3 |
Pagination | 980-7 |
Date Published | 1999 Mar |
ISSN | 0022-3042 |
Palabras clave | Amyloid beta-Protein Precursor, Astrocytoma, Brain Neoplasms, Carrier Proteins, Epidermal Growth Factor, Heparin, Humans, Neoplasm Proteins, Protease Nexins, Receptors, Cell Surface, Receptors, LDL, Serpin E2, Thrombin, Thrombomodulin, Tumor Cells, Cultured |
Abstract | Astroglial cells secrete a variety of factors that contribute to the regulation of neurite initiation and continued outgrowth, among them proteases and protease inhibitors. An alteration in the balance between these proteins has been implicated in Alzheimer's disease, resulting in an accumulation of thrombin:protease nexin 1 (PN1) complexes in the brains of these patients. This report aims at providing a biochemical explanation for this phenomenon. We show that human astrocytoma cells bind and internalize thrombin and thrombin:PN1 complexes efficiently by a PN1-dependent mechanism. Binding was potently inhibited by soluble heparin and did not occur with the mutant PN1 (K7E) deficient in heparin binding. Receptor-associated protein, an antagonist of the low-density lipoprotein receptor-related protein (LRP), inhibited internalization of thrombin by the astrocytoma cells, but did not affect cell-surface binding. The results are consistent with a mechanism by which astrocytoma cells clear thrombin in a sequential manner: thrombin is first complexed with PN1, then bound to cell-surface heparins, and finally internalized by LRP. This mechanism provides a link between the neuronal growth regulators thrombin and PN1 and proteins genetically associated with Alzheimer's disease, such as LRP. |
Alternate Journal | J. Neurochem. |
PubMed ID | 10037469 |
Grant List | AG1204 / AG / NIA NIH HHS / United States R01 GM34001 / GM / NIGMS NIH HHS / United States R01 HL47463 / HL / NHLBI NIH HHS / United States |