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AJAP1

Official Full Name
adherens junctions associated protein 1
Synonyms
AJAP1;adherens junctions associated protein 1;30801;ENSG00000196581;MOT8;SHREW1;SHREW-1;RP3-426F10.1;1p36.32;adherens junction-associated protein 1;adherens junction-associated protein 1;membrane protein shrew-1;transmembrane protein SHREW1;adherens junction associated protein 1;

Adherens junctional associated protein-1 (AJAP1), also known as SHREW1, was found on invasive endometriotic epithelial cells. Gene expression profiling showed that AJAP1 is located on chromosome 1p36.32, which is closely related to the weakening of tumor suppressor function. In recent years, many studies have shown that AJAP1 deletion has an important relationship with glioma progression. AJAP1 may play an important role in the development of glioma as a tumor suppressor gene.

AJAP1 is a complete transmembrane protein with 411 amino acid residues and its structure includes a separable N-terminal signal peptide (residues 1-43), extracellular domain (residues 44-282), transmembrane domain (residues 283-303), and intracellular cytoplasmic domains (residues 304-411). AJAP1 conforms to the structure of the long signal peptide required by the NtraC model: a subdomain of the N-amino terminus, a transition zone rich in β-turns, and a subdomain of the C-carboxy terminus. AJAP1 is localized on the cell basement membrane, and this long signal peptide structure determines the localization of AJAP1 in the cell, which can promote the targeting of the newly generated AJAP1 to the rough endoplasmic reticulum, and then transfer and localize on the cell membrane. Furthermore, the N-domain alone primarily targets AJAP1 to the mitochondria. This hidden mitochondrial targeting signal is only activated under certain physiological conditions, such as apoptosis. In the analysis of the AJAP1 protein sequence, it was found that the extracellular domain of AJAP1 has a nuclear localization signal and a glycosylation signal in the intracellular cytoplasmic domain.

Biological Function of AJAP1

Studies have demonstrated a transient expression of AJAP1 by confocal microscopy, indicating that AJAP1 colocalizes with endogenous E-cadherin on the cell basement membrane. In in vitro experiments, the researchers found that AJAP1 may link to E-cadherin-mediated junction complexes via β-catenin. Chen et al. found that methylation of AJAP1 may lead to the release of β-catenin and the activation of Wnt signaling. Studies have found that signaling pathways such as Wnt can inhibit GSK-3-mediated phosphorylation of β-catenin, shifting β-catenin to the nucleus and interacting with transcription factors to regulate gene transcription. AJAP1 translocates into the nucleus by β-catenin to regulate gene transcription, which may have a potential effect on cell cycle and apoptosis. Zeng et al. found that AJAP1 regulates the transcription of MAGEA2 gene in the nucleus. Moreover, AJAP1 regulates the P53 pathway to increase caspase-3/7 activity, affecting the Bax/Bcl-2 ratio. Therefore, AJAP1 can induce mitochondria-associated apoptotic pathway to regulate cell proliferation and apoptosis.

In addition, AJAP1 may be linked to E-cadherin-mediated junction complex via β-catenin. AJAP1 acts through the E-cadherin-β-catenin complex in polar cells, which has a role in altering the morphology of GBM cells. E-cadherin mediates the cytoskeleton to regulate cell adhesion by relating proteins such as α and β catenin. Confocal imaging showed that AJAP1 stably transfected GBM cells, and their cell morphology, F-actin and β-tubulin distribution were all changed. F-actin is the main component of the focal adhesion complex, which has effects on cell adhesion, migration, and promotion of filopodia. AJAP1 can inhibit the formation of filopodia, reduce the formation of filopodia, increase the lamellipodia and change the distribution of β-tubulin to promote cytoskeletal reorganization, loosening the cell network and inhibit cell invasion and migration.

Figure 1. A hypothetic model showing the role of AJAP1 in primary endothelial cells. (Hötte., et al. 2017)

AJAP1 and Glioma

AJAP1 expression was found to be reduced in most glioma tumors and glioma cell lines. Studies have used microsatellite and single nucleotide polymorphism techniques to analyze 430 primary neuroblastoma specimens and found the smallest common deletion locus located in the 2Mb region of 1p36 and identified 23 genes in this region, including AJAP1. In addition, there is minimal deletion region between oligodendroglioma chromosome 1p36.31-p36.32, including AJAP1. The investigators evaluated 177 oligodendroglioma samples and found a common deletion region of approximately 630 KB in size, which contains only the gene AJAP1. Moreover, Han et al found a loss of AJAP1 in the early stages of glioma development through glioma gene profiling, suggesting that glioma may be associated with AJAP1. Since the cells of common origin may have common genomic changes, the glioma genomes of different tissue types, pathological grades, and developmental stages all have the deletion of AJAP1 expression, indicating that AJAP1 may act as a tumor suppressor gene in the development of glioma. makes an important impact.

Most glioma tumors and cell lines did not find mutations in the coding region by sequencing the remaining alleles of AJAP1, suggesting a weak relationship between AJAP1 gene expression and loss of heterozygosity. AJAP1 expression was found to be reduced in 86% to 92% of primary high-grade gliomas and all glioma cell lines, while gene mutations were found in only 16% of glioma samples, revealing a decrease in AJAP1 expression caused by genetic silence in usual.

Ohgaki et al. found that there are many CpG islands in the promoter of AJAP1, and CpG island is a good site for methylation-regulated gene expression. Methylation results in epigenetic silencing, which is a gene regulation mechanism widely used in many tumors. AJAP1 may follow a similar chromosomal P16 tumor suppressor gene, and the gene mutation rate is lower due to promoter methylation. Mutation and methylation analysis confirmed that AJAP1 expression was determined by promoter methylation of epigenetic silencing. Some studies have analyzed 253 cases of oligodendroglioma in the cancer genome database, indicating that AJAP1 gene expression level is related to AJAP1 promoter methylation, and the degree of methylation is inversely proportional to AJAP1 expression.

AJAP1 promoter is highly methylated in most glioma cell lines, whereas CpG island methylation of the AJAP1 promoter in normal tissues is rare. In addition, glioma cells treated with demethylating agents AZA and TSA can effectively reverse this silencing mechanism of genes, restore AJAP1 expression levels, and significantly reduce the migration and invasion of glioma cells. The above indicates that methylation of the AJAP1 promoter results in epigenetic silencing, resulting in decreased expression of AJAP1 in gliomas.

References:

  1. Chen, Y. C., Huang, R. L., Huang, Y. K., Liao, Y. P., Su, P. H., & Wang, H. C., et al. (2014). Methylomics analysis identifies epigenetically silenced genes and implies an activation of β‐catenin signaling in cervical cancer. International Journal of Cancer, 135(1), 117-127.
  2. Zeng, L., Kang, C., Di, C., Fee, B. E., Rivas, M., & Lin, J., et al. (2014). The adherens junction-associated protein 1 is a negative transcriptional regulator of magea2, which potentiates temozolomide-induced apoptosis in gbm. International Journal of Oncology, 44(4), 1243-51.
  3. Han, L., Zhang, K. L., Zhang, J. X., Zeng, L., Di, C. H., & Fee, B. E., et al. (2014). Ajap1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization. Cns Neuroscience & Therapeutics, 20(5), 429.
  4. Ohgaki, H., & Kleihues, P. (2013). The definition of primary and secondary glioblastoma. Clinical Cancer Research An Official Journal of the American Association for Cancer Research, 19(4), 764-772.
  5. Hötte, K., Smyrek, I., Starzinski-Powitz, A., & Ehk, S. (2017). Endogenous ajap1 associates with the cytoskeleton and attenuates angiogenesis in endothelial cells. Biology Open, 6(6), 723-731.

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