MAGI3

Official Full Name

membrane associated guanylate kinase, WW and PDZ domain containing 3

Organism

Homo sapiens

GeneID

260425

Background

Predicted to enable frizzled binding activity. Predicted to be involved in signal transduction. Predicted to act upstream of or within positive regulation of JUN kinase activity. Located in cell junction. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

MAGI-3; dJ730K3.2;

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Detailed Information

The human MAGI family consists mainly of three members, MAGI1, MAGI2 and MAGI3, which are mainly expressed in epithelial cells and endothelial cells. MAGI3 contains two subtypes, MAGI3α and MAGI3β. Both MAGI3α and MAGI3β are mainly expressed on the cell membrane of epithelial cells, and a small amount is present in the cytoplasm.

Structure of MAGI3

Like other family members, MAGI3 consists of 5 to 6 PDZ domains, 2 WW domains, and 1 GK domain. The PDZ domain is named after members of the MAGUK family: PSD-95, Dlg, and ZO-1, which are widely found in various proteins and are one of the important structural domains of the MAGI family.

The PDZ domain usually has a certain selection specificity in mediating the interaction between different MAGI family members and different protein molecules. MAGI3 interacts with β- catenin via PDZ1 to PDZ4. Studies have shown that MAGI3 interacts with related protein molecules through its different PDZ domains, such as β1AR, β2AR, lysophosphatidic acid 2 (LPA 2), and transforming growth factor (TGF-α).

Currently, many proteins containing the WW domain have been shown to be involved in the development of a variety of tumors, such as tumor growth, migration and other malignant biological processes. MAGI3 interacts with the proline residue enrichment region of the target protein through the WW domain, eventually forming oligomers and exerting its biological functions.

Figure 1. Model for the mechanism by which premature polyadenylation of MAGI3 contributes to malignant transformation. (Ni, et al. 2016)

MAGI3 and Tumor

The main member of the MAGI family that plays a tumor suppressive role is MAGI3. It can inhibit the proliferation, migration and invasion of glioma cells. The specific molecular mechanism is divided into two aspects: On the one hand, PTEN is recruited to the cell membrane through its own PDZ domain. PTEN can dephosphorylate trisphosphoinositide (PIP3) on the cell membrane to form PIP2, which antagonizes the abnormal biological functions such as cell proliferation and migration induced by PI3K/Akt signaling pathway. On the other hand, through the interaction of MAGI3 and β-catenin at the cell membrane, it indirectly represses its nuclear translocation and inhibits the activation of Wnt/β-catenin signaling pathway, thereby exerting its tumor suppressive effect.

The study found that MAGI3 inhibits the development of colorectal cancer by competitively binding to lysophosphatidic acid 2 (LPA2) with Na+/H+ exchange regulatory factor (NHERF-2). MAGI3 specifically binds to four specific amino acid residues at the carboxy terminus of LPA2 through its PDZ5 domain, which binds NHERF-2 to LPA2, thereby inhibiting the downstream effects caused by the phosphatidylinositol signaling pathway and ultimately inhibiting the colorectal LPA2-induced migration and invasion in cancer cells. MAGI3 is a signaling pathway induced by inhibition of LPA2 in colorectal cancer.

Studies on a variety of malignancies have shown that non-synonymous substitution mutations and loss of copy number are rare in MAGI3. During the study of breast cancer, it was found that the concealed intron formed by premature division and polyadenylation resulted in truncated splicing of MAGI3 mRNA and lost the PDZ6 domain, while the PDZ6 domain of the carboxy terminus of MAGI3 was MAGI3. The molecular basis for interaction with YAP. Since the MAGI3 splice variant cannot interact with YAP, YAP can interact with other corresponding target proteins to form an active transcription factor, up-regulate the transcriptional expression level of the target gene, and ultimately lead to the malignant biological occurrence of breast cancer. The results suggest that MAGI3 may indirectly inhibit Hippo tumor signaling pathway by interacting with YAP, thereby reducing the incidence of breast cancer. MAGI3 inhibits the Hippo tumor signaling pathway in breast cancer.

References:

Ni, T. K. , & Kuperwasser, C. . (2016). Premature polyadenylation of magi3 produces a dominantly-acting oncogene in human breast cancer. eLife,5,(2016-05-19), 5, e14730.
Mosquera, J. M. , Varma, S. , Pauli, C. , Macdonald, T. Y. , Yashinskie, J. J. , & Varga, Z. , et al. (2015). Magi3–akt3 fusion in breast cancer amended. Nature, 520(7547), 11-2.
Zheng, S. , Zhao, C. L. H. , Feng, D. , Ma, Q. , He, J. , & Meng, R. , et al. (2015). Magi3 negatively regulates wnt/β-cateninsignaling and suppresses malignant phenotypes of glioma cells. Oncotarget, 6(34), 35851-35865.

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