The Physiological and Pathophysiological Roles of Melanotransferrin

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Melanotransferrin (MTf) is a membrane-bound molecule that was originally identified at very high levels in malignant melanoma cells and other tumours. To our surprise, our recent studies showed that MTf was also widely expressed in normal tissues (DR EJB 2000). MTf has many similarities to the iron (Fe)-binding protein, transferrin (Tf), and initially, MTf was thought to play a critical role in Fe uptake that is crucial for DNA synthesis. However, we demonstrated that MTf did not play a major role in Fe uptake by melanoma cells (DR 1990, 1991a,b, 2000). We also showed that the tissue distribution of MTf was very different to Tf and the Tf-receptor 1 (TfR1) that are well known to be involved in Fe transport. For instance, TfR1 is highly expressed in tissues with large Fe needs (e.g., placenta), while MTf is not expressed at high levels in these tissues and is found in unexpected locations (i.e., salivary gland). In contrast to expectations, MTf was also found at higher levels in normal than foetal tissue. Also interesting was the finding that MTf is found in the serum and brain of Alzheimer's disease patients. Over the last 2 years under our current NHMRC grant on MTf we have significantly extended our knowledge on this molecule. As proposed in this grant, we generated a MTf knockout mouse. This is a very exciting model that is the best way of determining the function of MTf. Furthermore, we used recombinant MTf to show that soluble MTf that is found in the plasma is not an effective Fe donor to cells (DR EJB 2002). Our results over the last 12 years indicate that MTf may play unexpected biological roles (see DR FEBS Lett 2000). For the first time, generation of our MTf knockout mouse will provide the exciting opportunity of characterising its role(s). This will be important in understanding the function of MTf in cancer cells, Alzheimer's disease and in other tissues (eg., salivary gland and kidney) where it is expressed at high levels.