Regulation of plasminogen activation: a role for melanotransferrin (p97) in cell migration

Abstract

We recently reported that human recombinant melanotransferrin (p97) presents a high transport rate across the bloodbrain barrier that might involve the lowdensity lipoprotein receptor-related protein (LRP). We now report new interactions between p97 and another LRP ligand, the urokinase plasminogen activator (uPA) complex. By using biospecific interaction analysis, both pro-uPA and plasminogen are shown to interact with immobilized p97. Moreover, the activation of plasminogen by pro-uPA is increased by soluble p97. Because the uPA system plays a crucial role in cell migration, both in cancer and in angiogenesis, we also measured the impact of both endogenous membrane-bound and exogenous p97 on cell migration.

Stimulation of cell surface plasminogen activation by membrane-bound melanotransferrin: A key phenomenon for cell invasion

“…However, the identities of cell surface binding sites for Plg have not been completely elucidated. The interaction between truncated sMTf and plasminogen, and its involvement in plasminogen activation stimulation by scu-PA was previously reported [27,28]. Thus, we now investigate whether mMTf could be a potential cell surface Plg binding and activation protein and determine its involvement in cell migration and invasion, by using control and MTf-transfected CHO cells as well as SK-Mel-28 melanoma cells.…”

“…Recent studies from our laboratory showed that truncated sMTf interacts with Plg and stimulates its activation by u-PA in vitro [27,28]. Here, the influence of mMTf expression on Plg binding at the cell surface was measured (Fig.…”

“…We have previously shown that human recombinant sMTf, which is a truncated form of mMTf, interacts with Plg and stimulates Plg activation by the urokinase-type PA (u-PA) [27,28]. Here, we investigated whether mMTf could bind to and stimulate Plg activation at the cell surface.…”

TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway

“…The observation that a protein involved in iron metabolism has a particular membrane localization is not novel because previous studies have shown that melanotransferrin, a transferrin homologue that binds iron, is attached to the cell surface via a GPI anchor (Food et al, 1994;Kennard et al, 1995). Interestingly, the function of melanotransferrin does not seem to be restricted to its capacity to act as an iron donor; indeed, membrane-bound melanotransferrin fulfils a regulatory function at the level of condrogenesis, angiogenesis, cell migration and tissue plasminogen activation (Sala et al, 2002;Demeule et al, 2003). Similarly, recent studies on TfR2, mainly based on the analysis of TfR2 mutant mice, indicate that TfR2 may function as a sensor of iron-saturated transferrin in the liver, where it acts upstream of hepcidin in the regulatory pathway of iron homeostasis (Kawabata et al, 2005).…”

Role of melanotransferrin in iron metabolism: studies using targeted gene disruption in vivo

“…4 Previous in vitro studies demonstrated that, although MTf could bind Fe, it did not efficiently donate it to the cell. [10][11][12][13] Many roles have been proposed for MTf, including transcytosis of Fe across the blood brain barrier, 14,15 angiogenesis, 16 cell migration, 16,17 plasminogen activation, 17 chondrogenesis, 18 eosinophil differentiation, 19 and Alzheimer's disease. 9,20 However, proof for the functional role of MTf is lacking.…”