IRCM, Inserm, ICM, Univ Montpellier, Montpellier, France.
Centre de Biologie Structurale (CBS), CNRS, INSERM, Univ Montpellier, Montpellier, France.
Sci Rep. 2021 Mar 11;11(1):5752. doi: 10.1038/s41598-021-85056-1.
Alterations to cell polarization or to intercellular junctions are often associated with epithelial cancer progression, including breast cancers (BCa). We show here that the loss of the junctional scaffold protein MAGI1 is associated with bad prognosis in luminal BCa, and promotes tumorigenesis. E-cadherin and the actin binding scaffold AMOTL2 accumulate in MAGI1 deficient cells which are subjected to increased stiffness. These alterations are associated with low YAP activity, the terminal Hippo-pathway effector, but with an elevated ROCK and p38 Stress Activated Protein Kinase activities. Blocking ROCK prevented p38 activation, suggesting that MAGI1 limits p38 activity in part through releasing actin strength. Importantly, the increased tumorigenicity of MAGI1 deficient cells is rescued in the absence of AMOTL2 or after inhibition of p38, demonstrating that MAGI1 acts as a tumor-suppressor in luminal BCa by inhibiting an AMOTL2/p38 stress pathway.
细胞极性或细胞间连接的改变通常与上皮癌的进展有关，包括乳腺癌（BCa）。我们在这里表明，连接支架蛋白 MAGI1 的缺失与管腔 BCa 的预后不良有关，并促进了肿瘤的发生。在 MAGI1 缺失的细胞中，E-钙粘蛋白和肌动蛋白结合支架 AMOTL2 积累，这些细胞受到增加的刚性。这些改变与低 YAP 活性有关，即 Hippo 通路的终末效应物，但 ROCK 和 p38 应激激活蛋白激酶活性升高。阻断 ROCK 可防止 p38 的激活，表明 MAGI1 通过释放肌动蛋白强度部分限制 p38 的活性。重要的是，在不存在 AMOTL2 或抑制 p38 的情况下，MAGI1 缺陷细胞的致瘤性增加得到挽救，这表明 MAGI1 通过抑制 AMOTL2/p38 应激通路在管腔 BCa 中作为肿瘤抑制因子发挥作用。
