Cellular mechanotransduction is a key informational system, yet its mechanisms remain elusive. Here we unveil the role of microtubules in mechanosignalling, operating downstream of subnuclear F-actin and nuclear envelope mechanics. Upon mechanical activation, microtubules reorganize from a perinuclear cage into a radial array nucleated by centrosomes. This structural rearrangement triggers degradation of AMOT proteins, which we identify as key mechanical rheostats that sequester YAP/TAZ in the cytoplasm. AMOT is stable in mechano-OFF but degraded in mechano-ON cell states, where microtubules allow AMOT rapid transport to the pericentrosomal proteasome in complex with dynein/dynactin. This process ensures swift control of YAP/TAZ function in response to changes in cell mechanics, with experimental loss of AMOT proteins rendering cells insensitive to mechanical modulations. Ras/RTK oncogenes promote YAP/TAZ-dependent tumorigenesis by corrupting this AMOT-centred mechanical checkpoint. Notably, the Hippo pathway fine-tunes mechanotransduction: LATS kinases phosphorylate AMOT, shielding it from degradation, thereby indirectly restraining YAP/TAZ. Thus, AMOT protein stability serves as a hub linking cytoskeletal reorganization and Hippo signalling to YAP/TAZ mechanosignalling.
© 2025. The Author(s).