ZIP4 Transporter

ZIP4 is a zinc transporter of the SLC39A family that facilitates the import of zinc into the cytoplasm. While essential for zinc homeostasis, overexpression of ZIP4 has been linked to cancer progression, including glioblastoma (GBM).

Full name: Zrt- and Irt-like Protein 4
Gene: SLC39A4
Protein family: ZIP (Zinc-Iron Permease), also called SLC39A family
Function: Imports extracellular or organellar zinc into the cytoplasm
Normal expression: Intestine (especially duodenum), pancreas, brain

Maintains intracellular zinc levels required for:
- Enzymatic activity
- Transcription factor function
- Immune cell signaling
Mutations in ZIP4 cause:
- Acrodermatitis enteropathica (rare congenital zinc deficiency)

ZIP4 signaling pathway

ZIP4 in Glioblastoma

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General Information

Name: ZIP4
Gene: SLC39A4
Family: ZIP (Zrt/Irt-like Protein) - SLC39 family
Function: Zinc transporter (Zn²⁺ influx into cytoplasm)
Location: Apical membrane of enterocytes (small intestine)

Physiological Role

ZIP4 plays a key role in zinc absorption from the diet. It is especially active during zinc deficiency. It is essential for:

Maintaining zinc homeostasis
Growth and development
Intestinal zinc uptake

ZIP4 is regulated by zinc levels:

↓ Zinc → ZIP4 expression ↑ and stabilized on membrane
↑ Zinc → ZIP4 internalized and degraded

Clinical Significance

Cause: Loss-of-function mutations in SLC39A4
Symptoms: Skin lesions, diarrhea, immune dysfunction
Treatment: Oral zinc supplementation

Overexpression of ZIP4 has been linked to:

Pancreatic cancer
Hepatocellular carcinoma
Esophageal cancer

ZIP4 contributes to:

Tumor cell proliferation and survival
Activation of STAT3, CREB
Upregulation of miR-373 → LATS2 inhibition → oncogenic YAP/TAZ signaling
Induction of IL-6 and VEGF → tumor progression

Pathways Activated

STAT3 → Cyclin D1, Bcl-2
CREB → miR-373 → ↓ LATS2
Pro-inflammatory / angiogenic signaling: IL-6, VEGF

Summary

ZIP4 is a zinc importer with essential physiological roles and important pathological implications, particularly in hereditary zinc deficiency and oncogenesis.