Ferroportin

Solute carrier family 40 (iron-regulated transporter), member 1
Identifiers
Symbols	SLC40A1 ; FPN1; HFE4; IREG1; MST079; MSTP079; MTP1; SLC11A3
External IDs	OMIM: 604653 MGI: 1315204 HomoloGene: 40959 GeneCards: SLC40A1 Gene
Gene ontology Molecular function • receptor activity • iron ion transmembrane transporter activity • protein binding • ferrous iron transmembrane transporter activity • peptide hormone binding • iron channel activity Cellular component • intracellular • cytoplasm • multivesicular body • plasma membrane • integral component of plasma membrane • synaptic vesicle • integral component of membrane • basolateral plasma membrane Biological process • lymphocyte homeostasis • endothelium development • cellular iron ion homeostasis • anatomical structure morphogenesis • regulation of transcription from RNA polymerase II promoter in response to iron • iron ion transmembrane transport • negative regulation of apoptotic process • positive regulation of transcription from RNA polymerase II promoter • transmembrane transport • spleen trabecula formation • multicellular organismal iron ion homeostasis • ferrous iron export Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	30061	53945
Ensembl	ENSG00000138449	ENSMUSG00000025993
UniProt	Q9NP59	Q9JHI9
RefSeq (mRNA)	NM_014585	NM_016917
RefSeq (protein)	NP_055400	NP_058613
Location (UCSC)	Chr 2: 189.56 – 189.58 Mb	Chr 1: 45.91 – 45.93 Mb
PubMed search	[1]	[2]

Ferroportin-1 also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 is a protein that in humans is encoded by the SLC40A1 gene. Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell.

Structure

Ferroportin-1 consists of 571 amino acid residues, with a highly conserved histidine at residue position 32. When mutated, lower activity in its iron transport role is observed.

Tissue distribution

Ferroportin is found on the surface of cells that store or transport iron, including:

• Enterocytes in the duodenum
• Hepatocytes
• Macrophages of the reticuloendothelial system.
• Adipocytes

Role in development

Ferroportin-1 plays an important role in neural tube closure and forebrain patterning.

Mouse embyros lacking the Scl40a1 gene are aborted before gastrulation occurs, proving that the Fpn1 protein encoded is necessary and essential for normal embryonic development. Fpn1 is expressed in the syncytiotrophoblast cells in the placenta and visceral endoderm of mice at E7.5. Further, several retrospective studies have noted an increased incidence of spina bifida occurring after low maternal intake of iron during embryonic and fetal development.

A recent study examining the consequences of several different mutations of the Slc40a1 mouse gene concluded that several serious neural tube and patterning defects were produced as a result, including spina bifida, exencephaly, and forebrain truncations, among others. Given the findings of studies to date, there appears to be significant evidence that intact iron transport mechanisms are critical to normal neural tube closure. Furthermore, other experiments have suggested that Fpn1 product and activity is required along the entire anterior-posterior axis of the animal to ensure proper closure of the neural tube.

Role in iron metabolism

Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalises it within the cell. This results in the retention of iron within enterocytes, hepatocytes, and macrophages with a consequent reduction in iron levels within the blood serum. This is especially significant with enterocytes which, when shed at the end of their lifespan, results in significant iron loss.

This is part of the mechanism that causes anaemia of chronic disease; hepcidin is released from the liver in response to inflammatory cytokines, namely interleukin-6, which results in an increased hepcidin concentration and a consequent decrease in plasma iron levels.

The ferroportin expression is also regulated by the IRP regulatory mechanism. If the iron concentration is too low, the IRP concentration increases, thus inhibiting the ferroportin translation. The ferroportin translation is also regulated by the micro RNA miR-485-3p.

Clinical significance

Mutations in the ferroportin gene are known to cause an autosomal dominant form of iron overload known as Type IV Haemochromatosis or Ferroportin Disease. The effects of the mutations are generally not severe but a spectrum of clinical outcomes are seen with different mutations. Ferroportin is also associated with African iron overload. Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. Both ferroportin and hepcidin are expressed in cultured human breast epithelial cells and hepcidin regulates ferroportin in these cells. Transfection of breast cancer cells with ferroportin significantly reduces their growth after orthotopic implantation in the mouse mammary fat pad. Ferroportin is a pivotal protein in breast biology and a strong and independent predictor of prognosis in breast cancer.

External links

• ferroportin1 protein at the US National Library of Medicine Medical Subject Headings (MeSH)