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Showing SLC39A4 — ZIP4 is a alias.

SLC39A4

Zinc transporter ZIP4 · UniProt Q6P5W5

Length
647 aa
Mass
68.4 kDa
Annotated
2026-06-10
30 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC39A4 (ZIP4) is the principal apical zinc uptake transporter of the small intestine and the primary genetic determinant of dietary zinc absorption (PMID:12068297, PMID:34843931). Its abundance is tuned to zinc status by layered post-transcriptional control: during zinc deficiency ZIP4 mRNA is stabilized and protein accumulates at the apical membrane, whereas zinc repletion drives ZIP4 internalization and lysosomal degradation (PMID:18020946). Under prolonged deficiency the extracellular N-terminal ectodomain is proteolytically cleaved at a metalloproteinase site following endocytosis and recycling, leaving the eight-transmembrane C-terminal half at the surface; acrodermatitis enteropathica mutations near this site block cleavage (PMID:18936158). Loss-of-function mutations in SLC39A4 cause acrodermatitis enteropathica, and disease alleles act by abolishing cell-surface expression and zinc transport (PMID:12068297, PMID:24586184). ZIP4 is essential for early embryonic development and for intestinal stem cell niche integrity, where its loss depletes Paneth cell labile zinc, reprograms Paneth cells toward a goblet-like state, and reduces crypt cell division and mTOR signaling (PMID:17483098, PMID:22737083). Aberrant ZIP4 overexpression in pancreatic, gallbladder, and gastric cancers raises intracellular zinc and promotes proliferation, migration, and resistance to copper-induced cuproptosis (PMID:18003899, PMID:33727860, PMID:42056258).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    Established the molecular identity of the intestinal zinc uptake transporter and linked it to a human disease, answering why acrodermatitis enteropathica disrupts zinc absorption.

    Evidence Chromosomal mapping, expression analysis, and mutational analysis in eight AE families

    PMID:12068297

    Open questions at the time
    • Did not define the transport mechanism or directionality biochemically
    • Did not address regulation by zinc status
  2. 2007 High

    Showed that ZIP4 abundance is dynamically matched to zinc availability through mRNA stability and protein trafficking, explaining how the transporter adapts to dietary zinc.

    Evidence In vivo dietary zinc manipulation in mice with immunofluorescence and mRNA stability assays in Hepa cells

    PMID:18020946

    Open questions at the time
    • Molecular machinery driving internalization/degradation not identified
    • Signal sensing zinc status not defined
  3. 2007 High

    Demonstrated that ZIP4 is required for early morphogenesis and that gene dosage governs sensitivity to maternal zinc deficiency, establishing its developmental essentiality.

    Evidence Homozygous and heterozygous Zip4 knockout mice with dietary zinc manipulation and developmental phenotyping

    PMID:17483098

    Open questions at the time
    • Tissue-specific contributions to lethality not dissected
    • Downstream zinc-dependent developmental pathways unresolved
  4. 2007 High

    Provided gain-of-function evidence that ZIP4-mediated zinc uptake drives tumor growth, opening a cancer-relevant axis for the transporter.

    Evidence Stable overexpression in pancreatic cancer cells with in vitro proliferation and xenograft models

    PMID:18003899

    Open questions at the time
    • Downstream signaling linking zinc to proliferation not identified
    • Endogenous regulation in tumors not addressed
  5. 2008 High

    Defined a second regulatory mechanism—proteolytic ectodomain cleavage during prolonged deficiency—and linked it to a disease mutation hotspot, refining how ZIP4 is processed at the membrane.

    Evidence In vivo intestinal analysis plus transfected MDCK/CaCo2/HEK293 cells with endocytosis inhibitors and disease-mutation analysis

    PMID:18936158

    Open questions at the time
    • Identity of the responsible protease not established
    • Functional consequence of the cleaved transporter on transport rate unresolved
  6. 2010 Medium

    Connected ZIP4 to cell survival and motility phenotypes, indicating roles beyond bulk zinc supply.

    Evidence RNAi knockdown and overexpression in Hepa and MCF-7 cells with cell cycle, apoptosis, and migration assays

    PMID:20957146

    Open questions at the time
    • No in vivo validation for these mechanisms
    • Molecular effectors of migration not identified
  7. 2012 High

    Revealed that intestinal ZIP4 maintains the stem cell niche by supplying labile zinc to Paneth cells and sustaining mTOR signaling, mechanistically grounding its intestinal essentiality.

    Evidence Tamoxifen-inducible enterocyte-specific Zip4 knockout mouse with histology, elemental analysis, and mTOR pathway assays

    PMID:22737083

    Open questions at the time
    • Mechanism coupling zinc to Paneth cell identity unknown
    • Direct link between zinc and mTOR attenuation not defined
  8. 2014 Medium

    Resolved how codon-372 variants alter function, distinguishing surface-expression loss as the basis of pathogenicity versus a partial-function polymorphism.

    Evidence Transient expression of ZIP4 variants in HeLa cells with surface expression and zinc uptake assays

    PMID:24586184

    Open questions at the time
    • Structural basis of trafficking defect not determined
    • Single cell-line context
  9. 2021 Medium

    Quantitatively established ZIP4 as the dominant transporter setting fractional dietary zinc absorption among all intestinal zinc transporters.

    Evidence 67Zn oral isotope absorption assay in mice with ICP-MS and qPCR profiling of 24 zinc transporters

    PMID:34843931

    Open questions at the time
    • Correlational design limits causal inference
    • Adult and human relevance not addressed
  10. 2021 Low

    Extended the pro-tumor role of ZIP4 to gallbladder cancer through standard loss/gain-of-function phenotyping.

    Evidence siRNA and overexpression in GBC-SD and NOZ cells with proliferation, migration, and xenograft assays

    PMID:33727860

    Open questions at the time
    • No specific pathway mechanism identified
    • Single lab, phenotype-only
  11. 2024 Low

    Placed SLC39A4 downstream of a transcriptional regulatory cascade in colorectal cancer, identifying an upstream activator and its mRNA stabilizer.

    Evidence Reporter assays, RNA immunoprecipitation, mRNA stability and knockdown/overexpression experiments in CRC cell lines

    PMID:38768927

    Open questions at the time
    • Single lab; mechanism of UKLF-driven SLC39A4 transcription not detailed
    • In vivo relevance not shown
  12. 2026 Medium

    Identified m6A-dependent stabilization of SLC39A4 mRNA by YTHDF1 and linked ZIP4 to suppression of copper-induced cuproptosis in gastric cancer, adding an RNA-modification regulatory layer and a metal-crosstalk function.

    Evidence Lentiviral overexpression/knockdown, m6A luciferase reporter mutagenesis, RIP, and cuproptosis assays in cells and xenografts

    PMID:42056258

    Open questions at the time
    • Mechanism by which zinc uptake counters cuproptosis not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical transport mechanism (stoichiometry, directionality, pore residues) and the identity of the protease and zinc-sensing machinery controlling ZIP4 trafficking remain undefined.
  • No reconstituted transport assay defining transport mechanism
  • Protease responsible for ectodomain cleavage unidentified
  • Zinc-status sensor governing mRNA stability and trafficking unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2 R-HSA-382551 Transport of small molecules 2

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 SLC39A4 encodes a ZIP-family zinc transporter protein expressed in the duodenum/jejunum; mutations in SLC39A4 cause acrodermatitis enteropathica, establishing it as the intestinal zinc uptake transporter responsible for this disease. Chromosomal mapping, expression analysis, and mutational analysis in eight AE-affected families Nature genetics High 12068297
2007 ZIP4 protein abundance is regulated post-transcriptionally: during zinc deficiency, ZIP4 mRNA stability increases and ZIP4 protein localizes to apical membranes; zinc repletion triggers ZIP4 internalization and degradation in enterocytes and visceral endoderm cells. In vivo dietary zinc manipulation in mice combined with immunofluorescence localization and mRNA stability assays in mouse Hepa cells Biological chemistry High 18020946
2007 Homozygous Zip4 knockout mouse embryos die during early morphogenesis, demonstrating that ZIP4 is essential for early embryonic development; heterozygosity causes hypersensitivity to zinc deficiency with developmental defects exacerbated by maternal zinc deficiency and ameliorated by zinc excess. Gene knockout mouse model with dietary zinc manipulation; developmental phenotyping Human molecular genetics High 17483098
2008 During prolonged zinc deficiency, the extracellular N-terminal ectodomain of ZIP4 is proteolytically cleaved, leaving the eight-transmembrane C-terminal half on the plasma membrane; this cleavage is blocked by acrodermatitis enteropathica mutations near a predicted metalloproteinase cleavage site and is attenuated by inhibitors of endocytosis, suggesting ectodomain cleavage occurs following internalization and recycling back to the plasma membrane. In vivo intestinal analysis and transfected MDCK, CaCo2, and HEK293 cell lines; inhibitor studies; disease mutation analysis Molecular and cellular biology High 18936158
2012 Enterocyte-specific knockout of Zip4 in mice causes loss of labile zinc in Paneth cells, reprogramming of Paneth cells toward a goblet cell-like state (loss of Sox9 and lysozyme, accumulation of mucin), dysplasia of intestinal crypts, diminished small intestine cell division, and attenuated mTOR1 activity in villus enterocytes indicative of increased catabolism, establishing ZIP4 as essential for intestinal stem cell niche integrity. Tamoxifen-inducible, enterocyte-specific Zip4 knockout mouse; immunohistochemistry; elemental analysis; mTOR pathway assay PLoS genetics High 22737083
2007 Forced overexpression of ZIP4 in pancreatic cancer cells increases intracellular zinc levels, increases cell proliferation ~2-fold in vitro, and dramatically increases tumor volume (13-fold) and peritoneal dissemination in xenograft mouse models, establishing a functional role for ZIP4-mediated zinc uptake in promoting tumor growth. Stable overexpression in pancreatic cancer cell lines; in vitro proliferation assay; subcutaneous and orthotopic xenograft mouse models Proceedings of the National Academy of Sciences of the United States of America High 18003899
2010 RNAi knockdown of Zip4 in mouse Hepa cells significantly increases apoptosis and slows G0/G1-to-S phase progression under zinc-deficient conditions; forced overexpression of Zip4 in Hepa and MCF-7 cells enhances in vitro migration, while knockdown depresses migration. RNAi knockdown; cell cycle analysis after hydroxyurea block; apoptosis assay; cell migration assay; forced overexpression PloS one Medium 20957146
2014 The Leu372Val polymorphism and disease-causing mutations Leu372Pro and Leu372Arg at the same codon differentially affect ZIP4 surface expression and zinc uptake: the two AE mutations abolish cell surface expression and nearly eliminate zinc uptake, while the Val372 variant shows significantly reduced surface protein expression, reduced basal intracellular zinc, and reduced zinc uptake compared to Leu372. Transient overexpression of ZIP4 variants in HeLa cells; surface protein expression assay; zinc uptake assay PLoS genetics Medium 24586184
2006 A splice-site variant in bovine SLC39A4 ortholog causes exon skipping, producing a protein predicted to lack two critical motifs in adjacent transmembrane domains implicated in forming the zinc transport pore, establishing loss of these transmembrane domains as the molecular basis of impaired zinc absorption in bovine hereditary zinc deficiency (lethal trait A46). Sequencing of bovine SLC39A4 ortholog; splice variant characterization; structural domain analysis Genomics Medium 16714095
2021 Among all intestinal zinc transporters, Slc39a4 expression is the only one positively correlated with fractional zinc absorption (liver and plasma 67Zn appearance), identifying SLC39A4/ZIP4 as the primary determinant of dietary zinc absorption in young mice. Stable isotope (67Zn) oral gavage absorption assay in mice fed varied zinc diets; ICP-MS measurement; qPCR expression profiling of all 24 zinc transporters across intestinal segments The Journal of nutritional biochemistry Medium 34843931
2021 SLC39A4 knockdown in gallbladder cancer cell lines suppresses proliferation, migration, and xenograft tumor growth, while overexpression promotes proliferation, migration, and inhibits apoptosis, indicating ZIP4 modulates survival and metastasis-related signaling in GBC cells. siRNA knockdown and overexpression in GBC-SD and NOZ cells; MTT assay; colony formation; wound-healing and Transwell migration assays; nude mouse xenograft Cancer management and research Low 33727860
2024 UKLF (ubiquitous Krüppel-like factor) transcriptionally activates SLC39A4 expression, while PCBP2 stabilizes UKLF mRNA by binding its 3'-UTR, placing SLC39A4 as a downstream transcriptional target in a PCBP2/UKLF/SLC39A4 pathway in colorectal cancer cells. Reporter assays, RNA immunoprecipitation, mRNA stability assay, knockdown/overexpression experiments in CRC cell lines Biochimica et biophysica acta. Molecular cell research Low 38768927
2026 YTHDF1 binds SLC39A4 mRNA and stabilizes its transcripts in an m6A-dependent manner (mutation of the m6A site in SLC39A4 coding sequence abolishes YTHDF1-mediated regulation); SLC39A4 overexpression attenuates cuproptosis induced by CuCl2/elesclomol treatment, while SLC39A4 knockdown potentiates it, establishing a role for ZIP4 in suppressing cuproptosis in gastric cancer cells. Lentiviral stable overexpression/knockdown; dual-luciferase m6A reporter assay; RNA immunoprecipitation for YTHDF1-SLC39A4 mRNA binding; proliferation and cuproptosis marker assays in cell lines and xenograft models Cancer gene therapy Medium 42056258

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nature genetics 355 12068297
2007 Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression. Proceedings of the National Academy of Sciences of the United States of America 221 18003899
2007 Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5). Biological chemistry 130 18020946
2012 A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity. PLoS genetics 107 22737083
2008 Novel proteolytic processing of the ectodomain of the zinc transporter ZIP4 (SLC39A4) during zinc deficiency is inhibited by acrodermatitis enteropathica mutations. Molecular and cellular biology 102 18936158
2007 The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency. Human molecular genetics 96 17483098
2009 An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Human mutation 94 19370757
2010 Zip4 (Slc39a4) expression is activated in hepatocellular carcinomas and functions to repress apoptosis, enhance cell cycle and increase migration. PloS one 70 20957146
2003 Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica. Human mutation 49 12955721
2003 Novel SLC39A4 mutations in acrodermatitis enteropathica. The Journal of investigative dermatology 45 12787121
2014 Extreme population differences in the human zinc transporter ZIP4 (SLC39A4) are explained by positive selection in Sub-Saharan Africa. PLoS genetics 30 24586184
2006 Identification of a unique splice site variant in SLC39A4 in bovine hereditary zinc deficiency, lethal trait A46: An animal model of acrodermatitis enteropathica. Genomics 24 16714095
2021 Slc39a4 in the small intestine predicts zinc absorption and utilization: a comprehensive analysis of zinc transporter expression in response to diets of varied zinc content in young mice. The Journal of nutritional biochemistry 18 34843931
2010 Congenital zinc deficiency from mutations of the SLC39A4 gene as the genetic background of acrodermatitis enteropathica. Journal of Korean medical science 15 21165302
2020 Analysis of the relationship between the mutation site of the SLC39A4 gene and acrodermatitis enteropathica by reporting a rare Chinese twin: a case report and review of the literature. BMC pediatrics 14 31987033
2015 Acrodermatitis Enteropathica: A Novel SLC39A4 Gene Mutation in a Patient with Normal Zinc Levels. Pediatric dermatology 14 25780817
2014 Effects of combined administration of rapamycin, tolvaptan, and AEZ-131 on the progression of polycystic disease in PCK rats. American journal of physiology. Renal physiology 13 24647711
2011 Novel SLC39A4 mutation in acrodermatitis enteropathica. Pediatric dermatology 10 22082465
2011 A Zinc Sulphate-Resistant Acrodermatitis Enteropathica Patient with a Novel Mutation in SLC39A4 Gene. JIMD reports 9 23430849
2010 One novel homozygous mutation of SLC39A4 gene in a Chinese patient with acrodermatitis enteropathica. Archives of dermatological research 9 20300938
2024 UKLF/PCBP2 axis governs the colorectal cancer development by transcriptionally activating SLC39A4. Biochimica et biophysica acta. Molecular cell research 8 38768927
2021 Knockdown of SLC39A4 Expression Inhibits the Proliferation and Motility of Gallbladder Cancer Cells and Tumor Formation in Nude Mice. Cancer management and research 8 33727860
2006 [Acrodermatitis enteropathica (AE) is caused by mutations in the zinc transporter gene SLC39A4]. Klinische Padiatrie 8 16819703
2022 Case report: Acrodermatitis enteropathica result from a novel SLC39A4 gene mutation. Frontiers in pediatrics 6 36479285
2011 Acrodermatitis enteropathica: a novel SLC39A4 gene mutation found in a patient with an early-onset. Pediatric dermatology 3 21906148
2017 [Analysis of SLC39A4 gene mutation in a patient with acrodermatitis enteropathica]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 28604961
2021 A Missense Variant in SLC39A4 in a Litter of Turkish Van Cats with Acrodermatitis Enteropathica. Genes 1 34573291
2026 YTHDF1/SLC39A4 signaling axis promotes gastric cancer cell proliferation by suppressing cuproptosis ex vivo and in vitro. Cancer gene therapy 0 42056258
2025 Heterozygous Variants of the SLC39A4 Gene and Possible Increased Risk for Developing Acrodermatitis Enteropathica with Kaposi's Varicelliform Eruption. The American journal of case reports 0 41385451
2014 SLC39A4 mutation in zinc deficiency patients. Journal of the Medical Association of Thailand = Chotmaihet thangphaet 0 25391167

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