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The HIPPO signaling pathway is a conserved tumor suppressor signaling pathway.Protein phosphatase 2A(PP2A)complex includes a family of protein serine/threonine phosphatases and their specificity were determined by combining different regulatory B subunits.In this research,the PP2A regulatory B subunit PPP2R2A was identified to negatively regulate HIPPO pathway in breast cancer cells,whose knockdown promoted the YAP phosphorylation and suppressed the cell proliferation and migration in breast cancer cells.The SBP-His-PPP2R2A tandem affinity purification(TAP)and LC/MS/MS mass spectrometry analysis showed that AMOTL2 was a potential partner of PPP2R2A breast cancer cells.Further investigation revealed that PPP2R2A dephosphorylated the AMOTL2 Ser-217 phosphorylation,and the AMOTL2 phosphorylation also activated the YAP phosphorylation and suppressed the breast cancer cell proliferation and migration.The activation of YAP phosphorylation by the PPP2R2A knockdown was blocked by the AMOTL2 knockdown and upregulation of YAP rescued the suppressive effects of PPP2R2A knockdown on the breast cancer cell proliferation and migration.Our results here suggest that PPP2R2A-containing PP2A complex negatively regulates HIPPO pathway by dephosphorylating AMOTL2 at Ser-217 in breast cancer cells.