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1 USA Cancer Center, University of South Alabama, Mobile, Alabama 36688; 2 Centocor Incorporated, Malvern, Pennsylvania 19355; and 3 Department of Biochemistry and Pediatrics, State University of New York, Buffalo, New York 14214
Separate pathways for transport of nontransferrin ferric and
ferrous iron into tissue cultured cells were demonstrated. Neither the
ferric nor ferrous pathway was shared with either zinc or copper.
Manganese shared the ferrous pathway but had no effect on cellular
uptake of ferric iron. We postulate that ferric iron was transported
into cells via 
3-integrin and mobilferrin (IMP), whereas
ferrous iron uptake was facilitated by divalent metal transporter-1
(DMT-1; Nramp-2). These conclusions were documented by competitive
inhibition studies, utilization of a 3-integrin antibody
that blocked uptake of ferric but not ferrous iron, development of an
anti-DMT-1 antibody that blocked ferrous iron and manganese uptake but
not ferric iron, transfection of DMT-1 DNA into tissue culture cells
that showed enhanced uptake of ferrous iron and manganese but neither
ferric iron nor zinc, hepatic metal concentrations in mk mice showing
decreased iron and manganese but not zinc or copper, and data showing
that the addition of reducing agents to tissue culture media altered
iron binding to proteins of the IMP and DMT-1 pathways. Although these
experiments show ferric and ferrous iron can enter cells via different
pathways, they do not indicate which pathway is dominant in humans.
mobilferrin; calreticulin; integrin; divalent metal transporter-1; Nramp-2
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