Zinc is an essential ion for cells with a vital role to play in controlling the cellular processes of the cell, such as growth, development and differentiation. Specialist proteins called zinc transporters control the level of intracellular zinc in cells. In mammals, the ZIP family of zinc transporters has a pivotal role in maintaining the correct level of intracellular zinc by their ability to transport zinc into cells from outside, although they may also transport metal ions other than zinc. There are now recognised to be four subfamilies of the ZIP transporters, including the recently discovered LIV-1 subfamily which has similarity to the oestrogen-regulated gene LIV-1, previously implicated in metastatic breast cancer. We call this new subfamily LZT, for LIV-1 subfamily of ZIP zinc Transporters. Here we document current knowledge of this previously uncharacterised group of proteins, which includes the KE4 proteins. LZT proteins are similar to ZIP transporters in secondary structure and ability to transport metal ions across the plasma membrane or intracellular membranes. However, LZT proteins have a unique motif (HEXPHEXGD) with conserved proline and glutamic acid residues, unprecedented in other zinc transporters. The localisation of LZT proteins to lamellipodiae mirrors cellular location of the membrane-type matrix metalloproteases. These differences to other zinc transporters may be consistent with an alternative role for LZT proteins in cells, particularly in diseases such as cancer.

The LIV-1 gene has been previously associated with oestrogen-positive breast cancer and its metastatic spread to the regional lymph nodes. We have investigated the protein product of this gene as a marker for disease progression of breast cancer. The protein sequence contains a potential metalloprotease motif (HEX P H E XGD), which fits the consensus sequence for the catalytic zinc-binding site motif of the zincin metalloproteases. This motif has identified a new subfamily of ZIP (Zrt-, Irt-like proteins) zinc transporters, which we have termed LZT (LIV-1 subfamily of ZIP zinc transporters). Expression of recombinant LIV-1 in Chinese-hamster ovary cells confirmed the prediction that LZT proteins can act as zinc-influx transporters. Zinc is essential for growth and zinc transporters have an important role in maintaining intracellular zinc homoeostasis, aberrations of which could lead to diseases such as cancer. This is the first report of the expression of a recombinant human LZT protein in mammalian cells. Recombinant LIV-1 locates to the plasma membrane, concentrated in lamellipodiae, similar to membrane-type metalloproteases. Examination of LIV-1 tissue expression located it mainly to hormonally controlled tissues with widespread expression in the brain. Interestingly, the LIV-1 sequence contains a strong PEST site and other potential degradation motifs, which, combined with our evidence that recombinant LIV-1 associates with ubiquitin, may explain the low-level expression of LIV-1. Combining the crucial role that zinc plays in cell growth and the proven role of metalloproteases in metastasis presents an exciting indication of how LIV-1 plays a role in breast cancer progression.

>sp|Q13433|S39A6_HUMAN Zinc transporter ZIP6 OS=Homo sapiens GN=SLC39A6 PE=1 SV=3
MARKLSVILILTFALSVTNPLHELKAAAFPQTTEKISPNWESGINVDLAISTRQYHLQQLFYRYGENNSLSVEGFRKLLQ
NIGIDKIKRIHIHHDHDHHSDHEHHSDHERHSDHEHHSEHEHHSDHDHHSHHNHAASGKNKRKALCPDHDSDSSGKDPRN
SQGKGAHRPEHASGRRNVKDSVSASEVTSTVYNTVSEGTHFLETIETPRPGKLFPKDVSSSTPPSVTSKSRVSRLAGRKT
NESVSEPRKGFMYSRNTNENPQECFNASKLLTSHGMGIQVPLNATEFNYLCPAIINQIDARSCLIHTSEKKAEIPPKTYS
LQIAWVGGFIAISIISFLSLLGVILVPLMNRVFFKFLLSFLVALAVGTLSGDAFLHLLPHSHASHHHSHSHEEPAMEMKR
GPLFSHLSSQNIEESAYFDSTWKGLTALGGLYFMFLVEHVLTLIKQFKDKKKKNQKKPENDDDVEIKKQLSKYESQLSTN
EEKVDTDDRTEGYLRADSQEPSHFDSQQPAVLEEEEVMIAHAHPQEVYNEYVPRGCKNKCHSHFHDTLGQSDDLIHHHHD
YHHILHHHHHQNHHPHSHSQRYSREELKDAGVATLAWMVIMGDGLHNFSDGLAIGAAFTEGLSSGLSTSVAVFCHELPHE
LGDFAVLLKAGMTVKQAVLYNALSAMLAYLGMATGIFIGHYAENVSMWIFALTAGLFMYVALVDMVPEMLHNDASDHGCS
RWGYFFLQNAGMLLGFGIMLLISIFEHKIVFRINF