Abstract
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 Centrin-2, predominantly at aberrant centrioles and unexpectedly even outside of mitosis. These findings reveal a GPER1-PKA-Centrin signaling axis in CRC cells that regulates centrosome numbers and centriole integrity, shedding light on centrosome abnormalities that drive neoplastic transformation and tumor progression.