Leguay, K. | Search bioRxiv

bioRxiv2023

The G protein-coupled receptor TBXA2R activates ERMs to promote motility, invasion, and metastasis of triple-negative breast cancer cells.

Cell migration and invasion are critical processes for cancer cell metastasis, relying on the ability of cells to adapt their morphology. Proteins of the ezrin, radixin, and moesin (ERM) family are key regulators of cell morphogenesis and essential determinants of cancer cell metastasis. However, the mechanisms by which ERMs are activated in metastatic cells remain poorly understood. Here, we identify the thromboxane A2 receptor (TBXA2R), a G protein-coupled receptor overexpressed in multiple cancers, as a critical activator of ERMs, enhancing the motility and invasion of triple-negative breast cancer (TNBC) cells. We found that TBXA2R activates ERMs by engaging the Gq/11 and G12/13 subfamilies, the small GTPase RhoA, and its Ser/Thr kinase effectors SLK and LOK. Furthermore, we demonstrate that TBXA2R promotes TNBC cell motility and invasion in vitro and metastatic colonization in vivo, dependent on ERM function. These findings reveal a novel signaling axis by which a member of the largest class of receptors activates key metastatic determinants, thereby controlling various aspects of metastasis. This discovery opens new avenues for developing targeted therapies against cancer metastasis.

cancer biology↗

bioRxiv2021

Interphase microtubule disassembly is a signaling cue that drives cell rounding at mitotic entry.

Reorganization of the cortical actin cytoskeleton at mitotic entry is essential to increase membrane tension for cell rounding1,2. This spherical shape is necessary for the biogenesis and organization of the mitotic spindle2-6. Proteins of the Ezrin, Radixin, Moesin (ERM) family play essential roles in mitotic morphogenesis by linking actomyosin forces to the plasma membrane2,3,7-10. While ERMs drive metaphase cell rounding, the cell-cycle signals that prompt their conformational activation in mitosis are unknown11. We screened a library of small molecules using novel ERM biosensors12 and we unexpectedly found that drugs that disassemble microtubules promote ERM activation. Remarkably, cells disassemble their interphase microtubules while entering mitosis13. We further discovered that this disassembly of microtubules acts as a cell-cycle signal that directs ERM activation and metaphase cell rounding. We show that GEF-H1, a Rho-GEF inhibited by microtubule binding, acts downstream of microtubule disassembly to activate ERMs via RhoA and its kinase effector SLK. In addition, we demonstrate that GEF-H1 and Ect2, another Rho-GEF responsible for the generation of mitotic actomyosin forces6,14, act together to drive metaphase ERM activation and cell rounding. In summary, we report microtubule disassembly as a cell cycle signal that triggers a signaling network ensuring that actomyosin forces are efficiently integrated at the plasma membrane to promote cell rounding at mitotic entry.

cell biology↗