Recombinant Human Metal cation symporter ZIP14 (SLC39A14), partial

Function

Electroneutral transporter of the plasma membrane mediating the cellular uptake of the divalent metal cations zinc, manganese and iron that are important for tissue homeostasis, metabolism, development and immunity (PubMed:15642354, PubMed:27231142, PubMed:29621230). Functions as an energy-dependent symporter, transporting through the membranes an electroneutral complex composed of a divalent metal cation and two bicarbonate anions (By similarity). Beside these endogenous cellular substrates, can also import cadmium a non-essential metal which is cytotoxic and carcinogenic (By similarity). Controls the cellular uptake by the intestinal epithelium of systemic zinc, which is in turn required to maintain tight junctions and the intestinal permeability (By similarity). Modifies the activity of zinc-dependent phosphodiesterases, thereby indirectly regulating G protein-coupled receptor signaling pathways important for gluconeogenesis and chondrocyte differentiation (By similarity). Regulates insulin receptor signaling, glucose uptake, glycogen synthesis and gluconeogenesis in hepatocytes through the zinc-dependent intracellular catabolism of insulin (PubMed:27703010). Through zinc cellular uptake also plays a role in the adaptation of cells to endoplasmic reticulum stress (By similarity). Major manganese transporter of the basolateral membrane of intestinal epithelial cells, it plays a central role in manganese systemic homeostasis through intestinal manganese uptake (PubMed:31028174). Also involved in manganese extracellular uptake by cells of the blood-brain barrier (PubMed:31699897). May also play a role in manganese and zinc homeostasis participating in their elimination from the blood through the hepatobiliary excretion (By similarity). Also functions in the extracellular uptake of free iron. May also function intracellularly and mediate the transport from endosomes to cytosol of iron endocytosed by transferrin (PubMed:20682781). Plays a role in innate immunity by regulating the expression of cytokines by activated macrophages (PubMed:23052185)

Subcellular Location

Cell membrane (Multi-pass membrane protein); Apical cell membrane (Multi-pass membrane protein); Basolateral cell membrane (Multi-pass membrane protein); Early endosome membrane (Multi-pass membrane protein); Late endosome membrane (Multi-pass membrane protein); Lysosome membrane (Multi-pass membrane protein)

Disease Association

Hypermanganesemia with dystonia 2 (HMNDYT2) : A metabolic autosomal recessive disorder characterized by increased blood manganese levels, neurodegeneration, and rapidly progressive parkinsonism and dystonia. Affected individuals present with loss of developmental milestones, progressive dystonia and bulbar dysfunction in infancy or early childhood. Towards the end of the first decade, they manifest severe generalized pharmacoresistant dystonia, spasticity, limb contractures and scoliosis, and loss of independent ambulation. Cognition may be impaired, but is better preserved than motor function. [The disease is caused by variants affecting the gene represented in this entry] | Hyperostosis cranialis interna (HCIN) : An autosomal dominant bone disorder characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base. The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII, its first symptoms often presenting during the second decade of life. [The disease is caused by variants affecting the gene represented in this entry. Conditional knockin mice overexpressing Arg-438 variant, which is the mouse equivalent of human variant Leu-441, in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients]

Tissue Specificity

Widely expressed but not detected in brain, heart, skeletal muscle, placenta and fetal skin

Subunit

Homotrimer

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• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• Nusbaum C. et al. DNA sequence and analysis of human chromosome 8. — Nature (2006)
• Mural R.J. et al. PubMed: CI-5GBD0VIIJ7C63 (SEP-)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Taylor K.M. et al. The LZT proteins; the LIV-1 subfamily of zinc transporters. — Biochim. Biophys. Acta (2003)
• Taylor K.M. et al. Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14. — FEBS Lett. (2005)
• Girijashanker K. et al. Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. — Mol. Pharmacol. (2008)