ZIP4 signaling pathway

The ZIP4 signaling pathway involves the ZIP4 transporter, a member of the Zrt/Irt-like Protein (ZIP) family encoded by the SLC39A4 gene. ZIP4 plays a central role in zinc uptake, especially in the intestine, but its dysregulation has also been linked to cancer progression, particularly pancreatic cancer and hepatocellular carcinoma.

🔬 Overview of the ZIP4 Signaling Pathway: 1. ZIP4 Function: ZIP4 transports extracellular zinc (Zn²⁺) into the cytoplasm.

It is upregulated under zinc deficiency.

Located predominantly on apical membranes of intestinal epithelial cells and in cancer cells under pathological conditions.

2. Upstream Regulation: Zinc deficiency or specific transcription factors (e.g., KLF4) can upregulate SLC39A4 gene expression.

Under certain stimuli, ZIP4 can be internalized or stabilized at the membrane.

3. Downstream Signaling Effects: Zinc influx via ZIP4 can activate multiple downstream pathways:

STAT3 (Signal Transducer and Activator of Transcription 3):

Zinc influx leads to STAT3 activation.

This promotes transcription of cell proliferation and survival genes (e.g., cyclin D1, Bcl-2).

CREB (cAMP response element-binding protein):

ZIP4 activation → CREB phosphorylation → transcription of miR-373.

miR-373:

Oncogenic microRNA upregulated by ZIP4 via CREB.

Suppresses LATS2 (a tumor suppressor in the Hippo pathway), enhancing YAP/TAZ oncogenic signaling.

IL-6 and VEGF Upregulation:

ZIP4 signaling increases pro-inflammatory and pro-angiogenic factors like IL-6 and VEGF, contributing to tumor microenvironment remodeling.

⚠️ In Disease Context: ZIP4 is overexpressed in several cancers, including:

Pancreatic ductal adenocarcinoma

Hepatocellular carcinoma

Esophageal cancer

In cancer, ZIP4 contributes to:

Enhanced zinc uptake

Increased cell proliferation

Promotion of epithelial-mesenchymal transition (EMT)

Resistance to apoptosis

🧬 Clinical Implications: ZIP4 is a potential biomarker and therapeutic target.

Targeting ZIP4 or its downstream effectors (e.g., STAT3, miR-373) could provide new avenues for anticancer therapies.