====== 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).

===== General Information =====
  * **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

===== Role in Zinc Homeostasis =====
  * 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 signaling pathway]]

===== ZIP4 in Glioblastoma (GBM) =====

[[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 ===

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

==== Cancer ====
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.