A molecular model for the tumour‐associated antigen, p97, suggests a Zn‐binding function

Garratt, Richard Charles; Jhoti, Harren

doi:10.1016/0014-5793(92)80654-y

Cited by 15 publications

(4 citation statements)

References 32 publications

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“…It has also been noted by some researchers that the Tf-independent Fe uptake pathway is inhibited by a number of transition metals (Wright et al, 1986;Morgan, 1988;Kaplan et al, 1991;Seligman et al, 1991;Olakanmi et al, 1994). Furthermore, based on a molecular model of p97, it appears that p97 has zinc binding properties (Garratt and Jhoti, 1992). This raises the question of whether the Tf-independent or p97-mediated Fe uptake pathway actually provides an alternate pathway for other metals to enter the cell non-competitively with Fe, which would enter the cell via the RME pathway.…”

Section: Discussionmentioning

confidence: 99%

A novel iron uptake mechanism mediated by GPI-anchored human p97.

et al. 1995

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The established process for iron uptake into mammalian cells involves transferrin and its receptor. Here, the role of the glycosyl‐phosphatidylinositol (GPI)‐linked transferrin homologue, melanotransferrin or p97, was studied using CHO cell lines defective in the transferrin receptor (TR) and transfected with human TR and/or human p97. The presence of p97 doubled the iron uptake, which could be explained by the binding of one atom of iron to one molecule of p97. The internalization of iron was shown to be temperature sensitive and saturated at a media iron concentration of 2.5 micrograms/ml with a Vmax of 0.1 pmol Fe/10(6) cell/min and a Km of 2.58 microM for p97. Treatment of the cells with either phosphatidylinositol‐phospholipase C or monoclonal antibodies against p97 resulted in over a 50% reduction and a 47% increase in the iron uptake respectively. These data identify p97 as a unique cell surface GPI‐anchored, iron binding protein involved in the transferrin‐independent uptake of iron in mammals.

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Section: Discussionmentioning

confidence: 99%

A novel iron uptake mechanism mediated by GPI-anchored human p97.

et al. 1995

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“…Elegant molecular modelling studies have demonstrated that a potential Zn(II)‐binding thermolysin consensus sequence in MTf is oriented in an appropriate stereochemical arrangement to allow it to bind Zn(II) that is crucial for metalloprotease activity [44]. Indeed, the Zn‐binding site responsible for catalytic activity in thermolysin is nearly superimposable on the MTf site [44]. Examining the MTf molecules found in a variety of species, only human MTf contains the consensus sequence HE XX H found in metallopeptidases such as thermolysin (Table 2).…”

Section: Possible Functional Roles Of Melanotransferrinmentioning

confidence: 99%

The membrane‐bound transferrin homologue melanotransferrin: roles other than iron transport?

Sekyere

Richardson

2000

FEBS Letters

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Melanotransferrin (MTf) is a membrane-bound transferrin (Tf) homologue that is found at high levels in melanoma cells. MTf has many characteristics in common with serum Tf and previous studies have shown that it can bind Fe. This has led to speculation that MTf may be involved in Fe transport. Because Fe is required for a variety of metabolic reactions including ATP and DNA synthesis, MTf could play a role in proliferation. However, recently it has been shown that MTf plays very little role in Fe uptake by melanoma cells, and unlike other Fe transport molecules (e.g. the transferrin receptor), its expression is not controlled by Fe. In the present review the function of MTf is discussed in relation to data suggesting other roles apart from Fe uptake. ß

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“…In fact, while no significant Zn(II)‐citrate‐transporting role of MTf was identified in our studies (Fig. 4), it has been suggested that the potential Zn(II)‐binding thermolysin consensus sequence in MTf may impart it with metalloprotease activity [46]. Considering our results, further studies have been initiated to examine the metalloprotease activity of MTf and to develop MTf knockout mice, both of which may provide clues to its biological role(s).…”

Section: Discussionmentioning

confidence: 63%

The role of the membrane‐bound tumour antigen, melanotransferrin (p97), in iron uptake by the human malignant melanoma cell

Richardson

2000

European Journal of Biochemistry

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Melanotransferrin (MTf) is a membrane‐bound transferrin (Tf) homologue with several characteristics in common with serum Tf. MTf is found at high levels in melanoma cells and previous studies have shown that MTf can bind Fe. In addition, Chinese hamster ovary cells transfected with MTf transport Fe from 59Fe‐citrate at greater rates than control cells. However, the role of MTf in the Fe uptake process of human melanoma cells remains unknown. In the present study we have characterized the role of MTf in Fe uptake by SK‐Mel‐28 melanoma cells in order to understand its function. Initial studies examined whether modulation of intracellular Fe levels using the Fe chelator desferrioxamine (DFO) or the Fe donor ferric ammonium citrate (FAC) could change MTf mRNA levels. In contrast to transferrin receptor (TfR) mRNA that increased after exposure to DFO and decreased after incubation with FAC, there was no change in MTf mRNA levels. In addition, compared to control cells, there was no alteration of 125I‐labelled anti‐MTf mAb‐binding in cells exposed to DFO or FAC, suggesting no change in the number of MTf sites. Further studies examined the ability of DFO and FAC to modulate Fe uptake from 59Fe‐citrate which is bound by MTf. In contrast to the effect of DFO or FAC at increasing and decreasing Fe uptake from 59Fe‐Tf, respectively, DFO had no influence on 59Fe‐citrate uptake, whereas FAC markedly increased it. Collectively, these studies suggest that MTf is not regulated in a manner similar to the TfR in response to cellular Fe levels. MTf can be removed from the membrane by phosphatidylinositol‐specific phospholipase C (PtdIns‐PLC). Preincubation of melanoma cells with PtdIns‐PLC reduced anti‐MTf mAb binding to 3% of the control, while PtdIns‐PLC only slightly reduced 59Fe uptake from 59Fe‐citrate. These results suggest that MTf played only a minor role in Fe uptake from 59Fe‐citrate by these cells. The expression of MTf mRNA (poly A+) was also examined in 50 human tissues and found to be markedly different to Tf mRNA or TfR mRNA. Surprisingly, MTf mRNA expression was widespread in normal tissues, and was observed at its highest levels in the salivary gland. In contrast to expectations, MTf mRNA expression was generally greater in adult than fetal tissues.

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A molecular model for the tumour‐associated antigen, p97, suggests a Zn‐binding function

Cited by 15 publications

References 32 publications

A novel iron uptake mechanism mediated by GPI-anchored human p97.

A novel iron uptake mechanism mediated by GPI-anchored human p97.

The membrane‐bound transferrin homologue melanotransferrin: roles other than iron transport?

The role of the membrane‐bound tumour antigen, melanotransferrin (p97), in iron uptake by the human malignant melanoma cell

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