ArticleInternational journal of biological sciences2026
AMOTL2 inhibits lymph node metastasis in gastric cancer by suppressing TGF-β/Smad signaling and is destabilized by the E3 ubiquitin ligase SMURF1.
Article in International journal of biological sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Angiomotin-like protein 2 (AMOTL2) regulates cell polarity and cytoskeletal regulation, but its role in gastric cancer (GC) remains undefined. Here, we show that AMOTL2 is frequently downregulated in GC tissues and cell lines, and its low expression is associated with deeper tumor invasion, lymph node metastasis, and shorter overall survival. Gain- and loss-of-function assays demonstrated that AMOTL2 suppresses GC cell proliferation, migration, and invasion. AMOTL2 overexpression also impaired endothelial and lymphatic-endothelial tube formation and reduced the expression of angiogenic and lymphangiogenic factors. In the subcutaneous, orthotopic, and popliteal lymph node metastasis models, AMOTL2 inhibited tumor growth and lymphatic dissemination. Mechanistically, AMOTL2 suppressed TGF-β/Smad signaling, as evidenced by reduced BMP2 and TGF-β1 expression, decreased Smad1/5/9 and Smad2/3 phosphorylation, and impaired Smads nuclear accumulation. Notably, pharmacological Smad1/5/9 activation by SB4 partially reversed the suppressive phenotypes of AMOTL2
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