Angiomotin Family Members: Oncogenes or Tumor Suppressors?

Abstract

Angiomotin (Amot) family contains three members: Amot (p80 and p130 isoforms), Amot-like protein 1 (Amotl1), and Amot-like protein 2 (Amotl2). Amot proteins play an important role in tube formation and migration of endothelial cells and the regulation of tight junctions, polarity, and epithelial-mesenchymal transition in epithelial cells. Moreover, these proteins regulate the proliferation and migration of cancer cells. In most cancers, Amot family members promote the proliferation and invasion of cancer cells, including breast cancer, osteosarcoma, colon cancer, prostate cancer, head and neck squamous cell carcinoma, cervical cancer, liver cancer, and renal cell cancer. However, in glioblastoma, ovarian cancer, and lung cancer, Amot inhibits the growth of cancer cells. In addition, there are controversies on the regulation of Yes-associated protein (YAP) by Amot. Amot promotes either the internalization of YAP into the nucleus or the retention of YAP in the cytoplasm of different cell types. Moreover, Amot regulates the AMPK, mTOR, Wnt, and MAPK signaling pathways. However, it is unclear whether Amot is an oncogene or a tumor suppressor gene in different cellular processes. This review focuses on the multifunctional roles of Amot in cancers.

Keywords: Angiomotin; YAP.; cancer; oncogene; tumor suppressor.

Figure 1

Domain structures of proteins from the Amot family (Amot-p80, Amot-p130, Amotl1, and Amotl2).

Figure 2

Schematic models for YAP regulation by Amot. (A). Amot-p130 facilitates the nuclear entry and transcriptional activity of YAP, promoting the transcription of TEAD-target genes. (B) Amot binds to Merlin at the tight junctions and phosphorylates Mst1/2, LATS1/2, and Mob1. Phosphorylated LATS1/2 phosphorylates YAP, which promotes the ubiquitination and degradation of YAP. (C) Amot promotes the phosphorylation of YAP by LATS2 in the cytoplasm, leading to YAP degradation. (D) LATS-mediated phosphorylation of Amot promotes the interaction between Amot and YAP and subsequent degradation of YAP. (E) F-actin and YAP compete for binding to Amot at the tight junctions. Amot binds to YAP and maintains in the cytoplasm. (F) Amot physically interacts with YAP leading to localization to the actin cytoskeleton.