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Angiomotin (AMOT) is an angiostatin-binding protein consisting of 675 amino acid residues located at Xq23 of the chromosome. Its family includes new proteins of Angiomotin and Angiomotin-like structures - Angiomotin-like protein 1 (AMOTL1) and Angiomotin-like protein 2 (AMOTL2). Studies have shown that family members have variable splice sites and form different subtypes of proteins with different functions; AMOT has two isoforms P80-AMOT and P130-AMOT, P80-AMOT can be enhanced the migration of cells and be localized to the apical pseudopod front and stabilized the tubular structure, while P130-AMOT is associated with actin and affects cell shaping. The role of AMOT family proteins is mainly involved in the formation of ducts, cell migration, cell proliferation, and polarity. In recent years, AMOT has been found to be closely related to tumor proliferation, invasion, and metastasis.
Expression of AMOT in Tumors and Its Relationship with Tumorigenesis and Development
At present, some studies have found that AMOT is highly expressed in some tumors, and its high expression promotes tumor proliferation, invasion and metastasis. Byun et al. found high expression of AMOT in inverted papilloma of the nasal cavity and paranasal sinus, suggesting that it may be closely related to the proliferation and development of inverted papilloma. In addition, AMOT is highly expressed in osteosarcoma and osteosarcoma cell SAOS-2, MG-63, U-2 OSs. After inhibition of AMOT expression in Mg-63 by RNA interference, the proliferation of the cells was inhibited and the invasion and metastasis ability was reduced.
Further studies found that in the mouse model of Nf2 knockout liver cancer, the expression of AMOT in the hepatocarcinoma tissues was significantly higher than that in the adjacent tissues. At the same time, immunohistochemistry was used to find high expression of AMOT in Nf2 mutant Schwann cells.
Lv and other studies found that AMOT is highly expressed in breast cancer tissues but is low in adjacent tissues, and its expression level is related to Ki-67. Knockout of the AMOT gene in breast cancer cell MCF-7 resulted in a significant decrease in the proliferation and invasion of cancer cells. The team continued to study that the proliferation of both cells was also inhibited after silencing the expression of AMOT in renal tubular epithelial cells HK-2 and renal cancer cells 786-O. After up-regulating the AMOT expression in renal cell carcinoma ACHN, the proliferation of the cells was significantly increased. These have fully proved that AMOT has promoted the occurrence and development of tumors.
However, studies have also shown that AMOT is lowly expressed in tumors, and its low expression is associated with high proliferation, high invasion, and metastasis ability of tumors. Adler et al. showed that AMOT130 inhibits the growth of breast cancer MDA-MB-468 cells. It is possible that AMOT has a different role in different types of breast cancer cells, and it may be that different AMOT subtypes play different roles. In addition, Hsu et al found that AMOT is underexpressed in lung cancer tissues and high invasive lung cancer cells LLC. After inhibiting AMOT expression in low invasive lung cancer cell line CL1-0 by RNA interference, BrdU method was used to detect the proliferation of CL1-0 cells, and the invasion and migration ability of scar test and Transwell assay was significantly enhanced. The AM1 knockout LLC1 cells were injected into the skin of mice, and the growth rate and invasion and metastasis ability of the mice in the experimental group were significantly enhanced compared with the control group. At present, there are few studies on the relationship between AMOT and lung cancer, and the results need to be verified by repeated experiments. The expression and function of AMOT may be different in different cell lines.
Mechanism of Action of AMOT in Tumors
The mechanism of action of AMOT in tumors is complex and related to a variety of factors. However, more research is on the relationship between AMOT and Hippo-YAP pathways. Yes-associated protein (YAP) is the core effector of the Hippo-YAP pathway and is an intracellular connexin and transcriptional coactivator. It mainly binds to the nuclear transcription factor TEAD, activates transcription of downstream related genes, promotes cell growth, and inhibits apoptosis. Abnormalities in any factor in the Hippo-YAP pathway will break the balance between cell proliferation and apoptosis and promote tumorigenesis and development.
Figure 1. Schematic models for YAP regulation by Amot. (Lv, et al. 2015).
Adler et al. used HEK-293T, MCF-7 and MDA-MB-468 cells to find that AMOT binds to AIP4 (atrophin-1 interacting protein 4) and activates its expression, making it ubiquitinated with YAP, resulting in AMOT stabilization and YAP Degradation. The two act together to inhibit the expression of YAP and inhibit the growth of tumor cells. These studies demonstrate that AMOT has a function of inhibiting tumorigenesis and development via the YAP pathway.
However, as the research progresses, some scholars believe that AMOT plays a role in promoting cell proliferation, invasion and metastasis through the interaction with YAP during tumor development. Lv et al. inhibited the expression of AMOT in breast cancer cells MCF-7 and found that the expression of YAP, YAP / TAZ and LATS1 (large tumor suppressor homology 1) was also down-regulated. This suggests that AMOT may affect breast cancer proliferation and invasion through the Hippo-YAP signaling pathway. Yi et al. found that P130-AMOT is required for YAP-mediated hepatic epithelial cell proliferation and tumor formation. The PPxY and LPxY domains of P130-AMOT bind to YAP and the WW domain, inhibiting phosphorylation caused by binding of cytosolic YAP to the WW domain on LATS1, and a decrease in phosphorylation may cause YAP to be transferred into the nucleus. P130-AMOT in the nucleus forms a complex with YAP and TEADs and is involved in the regulation of a subset of the YAP target gene, which includes many genes involved in tumorigenesis. Therefore, this study suggests that AMOT acts as a cofactor for YAP, preventing YAP phosphorylation and increasing its activity against a specific set of tumor-promoting genes.
Moleirinho et al. believe that AMOT family members regulate YAP expression through three negative regulatory pathways and one positive regulatory pathway: (1) AMOT-mediated phosphorylation by AMTS promotes AMOT-YAP combination, followed by inhibition of YAP activity; (2) AMOT as a tight junction (TJ) scaffold protein, carrying MST and LATS, promoting LATS activity and LATS-mediated YAP phosphorylation; (3) AMOT interaction with YAP leads to localization to TJ or actin cytoskeleton and it is independent of LATS-mediated phosphorylation; (4) AMOT-P130 interaction with YAP inhibits its phosphorylation with LATS1/2 mediated YAM, followed by AMOT-P130: YAP complex entering the nucleus to promote TEAD target Transcription of genes.