biostudies-literatureFahrlander JDeutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)1739https://www.ebi.ac.uk/biostudies/studies/S-EPMC12673129biostudies-literatureUnknown8(1)Centrosome amplification is a hallmark of colorectal cancer (CRC), yet its molecular origins remain elusive. Protein Kinase A (PKA), anchored to centrosomes, regulates a number of mitotic processes, though its role in maintaining centrosome integrity remains poorly understood. Here, we show that PKA is central to a signaling cascade involving the G protein-coupled estrogen receptor GPER1, which is essential for centrosome integrity in colon cancer cells. Activation of GPER1 by estrogens or a specific agonist triggers Gαs protein-mediated stimulation of adenylyl cyclase, elevating cAMP levels and thereby increasing PKA activity. Excessive activation of GPER1-PKA leads to extra centrosomes with enlarged, displaced Centrin-2 foci. Recruited to centrosomes by AKAP450, PKA phosphorylates CentriCommunications biologyA GPER-PKA-Centrin axis regulates centrosome numbers and centriole integrity in colon cancer cells.PMC12673129465732234; STO 1306/2-1Buhler MBusse MBecker MShih JMStolz AFahrlander JSchonfelder GZordick CfalseA GPER-PKA-Centrin axis regulates centrosome numbers and centriole integrity in colon cancer cells.Centrosome amplification is a hallmark of colorectal cancer (CRC), yet its molecular origins remain elusive. Protein Kinase A (PKA), anchored to centrosomes, regulates a number of mitotic processes, though its role in maintaining centrosome integrity remains poorly understood. Here, we show that PKA is central to a signaling cascade involving the G protein-coupled estrogen receptor GPER1, which is essential for centrosome integrity in colon cancer cells. Activation of GPER1 by estrogens or a specific agonist triggers Gαs protein-mediated stimulation of adenylyl cyclase, elevating cAMP levels and thereby increasing PKA activity. Excessive activation of GPER1-PKA leads to extra centrosomes with enlarged, displaced Centrin-2 foci. Recruited to centrosomes by AKAP450, PKA phosphorylates Centri2025-01-01T00:00:00Z2025 Nov2026-06-06T07:37:58.426Z2026-06-06T03:06:38.401ZS-EPMC126731294129915510.1038/s42003-025-09249-4